Organic reactions carried out in aqueous solution in the presence of a hydroxyalkyl(alkyl)cellulose or an alkylcellulose

ABSTRACT

The present invention relates to a method of carrying out an organic reaction in aqueous solution in the presence of a hydroxyalkyl(alkyl)cellulose or an alkylcellulose.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/742,523, filed Jan. 14, 2020, which is a continuation of U.S. patentapplication Ser. No. 16/434,900, filed Jun. 7, 2019, which is acontinuation of U.S. patent application Ser. No. 15/417,806, filed Jan.27, 2017, which claims the benefit of U.S. Patent Application No.62/288,890, filed Jan. 29, 2016, and International Patent ApplicationNo. PCT/EP2016/053238, filed Feb. 16, 2016, the contents of all of whichare fully incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a method of carrying out an organicreaction in aqueous solution in the presence of ahydroxyalkyl(alkyl)cellulose or an alkylcellulose.

BACKGROUND OF THE INVENTION

With the growing concern for environmental protection, chemicalsynthesis and process chemistry are increasingly scrutinized withrespect to sustainability. The term “green chemistry” illustrates thegoal to provide a more resource-efficient and inherently safer design ofmolecules, materials, products, and processes. One goal is to providechemical processes which minimize the use of substances which do notorigin from renewable sources and/or cause disposal problems. Especiallyreducing or avoiding the use of organic solvents is the primaryobjective, as these account for the major part of the feedstock used inmany chemical processes. Most organic solvents are of mineral origin andthus not from a renewable source. They are rather expensive, not onlybecause of their production costs, but also because of the costs relatedwith their disposal. They often pose significant risks to theenvironment and humans handling them, being mostly flammable or evenexplosive, and need to be handled and stored with precaution.

Many efforts have therefore been made to replace at least a part of theorganic solvents with water. Water is readily available, cheap, neitherflammable nor explosive, and non-toxic. Unfortunately however, it hasonly poor solubility for most organic compounds, so that reaction timesand yields are generally inefficient. Many reactants agglomerate inaqueous medium, which hampers their efficient reaction and makes theirprocessing, especially stirring, difficult.To enhance conversion rates and reduce reaction times in aqueous medium,surfactants and emulsifiers are often used.Lipshutz and coworkers developed surfactants based onpolyoxyethanyl-α-tocopheryl succinate (TPGS-750-M and TPGS-1000) orsebacate (PTS-600) which in aqueous solution forms micelles in whichorganic reactions can take place. TPGS-750-M, which is the mostpromising, is a polyoxyethanyl-α-tocopheryl succinate derivative offollowing formula:

The use of these micelle-forming surfactants is described, for example,in J. Org. Chem., 2011, 76 (11), 4379-4391 or Green Chem. 2014, 16,3660-3679, where the authors report the performance of variousreactions, including Heck, Suzuki-Miyaura, Sonogashira, and Negishi-likecouplings, as well as aminations, C—H activations, and olefin metathesisreactions in water in the presence of TPGS-750-M.While the results obtained with this surfactant are impressive,TPGS-750-M as well as the other polyoxyethanyl-α-tocopheryl derivativesare a rather expensive and sophisticated material. Moreover, they tendto agglomerate in the aqueous reaction medium, which hampers theefficient reaction of the reactants and makes their processing,especially stirring, difficult.Cellulose and its derivatives are inexpensive and biodegradable. Organicreactions in water catalyzed by a transition metal and carried out inthe presence of cellulosic material have been reported.Cellulose as such is not water-soluble or swellable and thus cannot actas a surfactant. It is used as carrier for transition metal catalysts;see for example

-   -   Baruah et al., Catalysis Commun. 2015, 69, 68-71, where        cellulose-supported copper nanoparticles are used as a catalyst        for the protodecarboxylation and oxidative decarboxylation of        aromatic acids; water or acetonitrile being used as solvents;    -   Baruah et al., Tetrahedron Lett. 2015, 56, 2543-2547, where        cellulose-supported copper nanoparticles are used as a catalyst        for the selective oxidation of alcohols to aldehydes; water or        acetonitrile being used as solvents;    -   Baruah et al., RSC Adv. 2014, 4, 59338-59343, where        cellulose-supported copper nanoparticles are used as a catalyst        for the deprotection of oximes, imines and azines to carbonyl;        water being used as solvent;    -   Chavan et al., RSC Adv. 2014, 4, 42137-42146, where        cellulose-supported CuI nanoparticles are used as a catalyst for        the one-pot synthesis of 1,4-disubstituted 1,2,3-triazoles in        water; and    -   Jamwal et al., Internat. J. Biol. Macromolecules 2011, 49,        930-935, where cellulose-supported Pd(0) is used as a catalyst        for Suzuki coupling and aerobic oxidation of benzyl alcohols in        water.        Modified celluloses are also used as carriers for transition        metal catalysts; see for example    -   Bhardwaj et al., where Pd(0) nanoparticles supported on ethylene        diamine functionalized silica cellulose is used as a catalyst        for C—C and C—S coupling reactions in water;    -   Faria et al., RSC Adv. 2014, 4, 13446-13452, where cellulose        acetate-supported Pd(0) nanoparticles are used as a catalyst for        Suzuki reactions in water,    -   Xiao et al., Appl. Organometal Chem. 2015, 29, 646-652, where        carboxymethyl cellulose-supported Pd nanoparticles are used as a        catalyst for Suzuki and Heck couplings in water;    -   Huang et al., Beilstein J. Org. Chem. 2013, 9, 1388-1396, where        Au nanoparticles covalently bonded to thiol-functionalized        nanocrystalline cellulose films are used as a catalyst for A³        coupling in water;    -   Keshipour et al., Cellulose 2013, 20, 973-980, where Pd(0)        nanoparticles supported on ethylene diamine functionalized        cellulose is used as a catalyst for Heck and Sonogashira        couplings in water;    -   Harrad et al., Catalysis Commun. 2013, 32, 92-100, where        colloidal Ni(0) carboxymethyl cellulose particles are used as a        catalyst for hydrogenation of nitro aromatic compounds and        carbonyl compounds in aqueous medium;    -   Zhang et al., Catal. Sci. Technol. 2012, 2, 1319-1323, where        sodium carboxymethyl cellulose-stabilized Pd is used as a        catalyst for the selective hydrogenation of acetylene in water;    -   Azetsu et al., Catalysis 2011, 1, 83-96, where Au/Pd bimetallic        nanoparticles supported on TEMPO-oxidized cellulose nanofibers        are used as a catalyst in the aqueous reduction of        4-nitrophenol; and    -   Lam et al., Nanoscale 2012, 4, 997, where Au nanoparticles        supported on poly(diallyldimethylamoniumchloride)-coated        nanocrystalline cellulose are used as a catalyst in the aqueous        reduction of 4-nitrophenol.        These documents do however not use the modified celluloses as        surfactants.        It was the object of the present invention to provide a        surfactant which allows the performance of organic reactions in        water with good yields and short reaction times, but which is        less expensive than TPGS-750-M and the other        polyoxyethanyl-α-tocopheryl derivatives described above, and        which is readily available. Moreover, this surfactant should not        be restricted to the application in transition metal-catalyzed        reactions, but should be widely applicable. Furthermore, the        surfactant should be easily separable from the reaction medium        after completion of the reaction.        The present invention is based on the finding that        hydroxyalkyl(alkyl)celluloses and alkylcelluloses solve this        task.

SUMMARY OF THE INVENTION

The invention relates to a method of carrying out an organic reaction ina solvent containing at least 90% by weight, in particular at least 97%by weight, based on the total weight of the solvent, of water, whichmethod comprises reacting the reagents in said solvent in the presenceof a cellulose derivative which is selected from the group consisting ofcellulose modified with one or more alkylene oxides or otherhydroxyalkyl precursors, and alkylcellulose;

where the organic reaction is not a polymerization or oligomerizationreaction of olefinically unsaturated compounds.

The invention also relates to the use of a cellulose derivative which isselected from the group consisting of cellulose modified with one ormore alkylene oxides or other hydroxyalkyl precursors, andalkylcellulose, as a surfactant in organic reactions carried out in asolvent containing at least 90% by weight, in particular at least 97% byweight, based on the total weight of the solvent, of water,where the organic reactions are not a polymerization or oligomerizationreaction of olefinically unsaturated compounds.

DETAILED DESCRIPTION

The below remarks and details of suitable and preferred or particularembodiments of the method of the invention are valid both alone, takenper se, and in particular in any conceivable combination with oneanother.

“Carrying out an organic reaction in a solvent containing at least 90%by weight, in particular at least 97% by weight, based on the totalweight of the solvent, of water” means that at least the principalreaction step of the organic reaction is carried out in said aqueousmedium. The aqueous medium is not limited to be used in a work-up orpurification or separation step.

Work-up, separation and purification can however encompass the use oforganic solvents.

The term “organic reaction” relates to all types of chemical reactionsinvolving at least one organic compound. Organic compounds in turn aregaseous, liquid, or solid chemical compounds whose molecules containcarbon. Exceptions are carbides, carbonates (in the sense of salts ofcarbonic acid), carbon oxides (CO and CO₂), and cyanides (in the senseof salts of HCN), which for historical reasons are considered asinorganic. The basic types of organic reactions are addition reactions,elimination reactions, substitution reactions, pericyclic reactions,rearrangement reactions, photochemical reactions and redox reactions.Further details will become evident in the detailed description below.

In terms of the present invention, the organic reactions do not includepolymerization or oligomerization reactions of olefinically unsaturatedcompounds, such as the polymerization of olefins (e.g. ethylene) topolyolefins (e.g. polyethylene), of acrylic acid (esters) topolyacrylates etc. In particular, in the present invention, the organicreactions do not include any type of polymerization or oligomerization,be it the polymerization of olefinically unsaturated molecules,polycondensations (like the formation of polyesters from diols anddiacids or derivatives thereof, or of polyamides from diamines anddiacids or derivatives thereof), or polyadditions (like the formation ofpolyurethanes). Polymerizations are reactions in which polymers areformed. Polymers in turn are high molecular mass compounds formed bypolymerization of monomers and contain repeating units of the same orsimilar structure. In terms of the present invention, polymers arecompounds formed of at least 11 monomers in polymerized form. Oligomers,too, are formed by polymerization of monomers and contain repeatingunits of the same or similar structure. They differ from polymers inbeing shorter-chained. In terms of the present invention, oligomerscontain 3 to 10 monomers in polymerized form.

Organic reactions which do not include any polymerization oroligomerization reaction yield compounds with a discrete (i.e.well-defined) molar mass. In contrast thereto, oligomers and polymers donot have a discrete molar mass, but a mass distribution. The ratio ofweight-average molecular weight and number average molecular weightM_(w)/M_(n) for polymers and oligomers is >1. Thus, the particularembodiment of the present method which excludes any type ofpolymerization or oligomerization, yields compounds with a well-definedmolar mass, and not with a molar mass distribution.

Apart from not including polymerization and oligomerization reactions ofolefinically unsaturated compounds and especially not including any typeof polymerization and oligomerization reactions at all, one otherlimiting factor imposed to the organic reactions which can be used inthe method of the present invention is reactants, intermediates andproducts which are too hydrolabile, i.e. which are too easilydeteriorated (e.g. hydrolyzed) by water to give satisfactory yields (ascompared to non-aqueous systems) under the given reaction conditions.Thus, the present method does not include organic reactions using oryielding compounds which are easily deteriorated by water under thegiven reaction conditions. It has has however to be noticed that not allreactions usually known to use or yield hydrolabile compounds areexcluded: Surprisingly, the method of the invention leads to good yieldsin a number of reactions which a skilled person would normally havecarried out under the exclusion of water. Another limiting factorimposed to the organic reactions which can be used in the method of thepresent invention is reaction temperatures distinctly below 0° C. (ithas to be mentioned that the addition of salts such as NaCl may allow tocarry out the reactions at temperatures somewhat below 0° C. as theylower the freezing point, e.g. to as low as −5° C. or even −10° C.) aswell as above the gelling or gelation point of the cellulose derivativeused (if this has a gelation point at all) under the respective reactionconditions (especially concentration of the cellulose derivative). Whenthe solutions of certain cellulose derivatives heat up to a criticaltemperature, the solutions congeal into a non-flowable, semi-flexiblemass and the reactions cannot proceed in an optimum way. Thus, thepresent method does not include organic reactions mandatorily andinevitably requiring reaction temperatures of distinctly below 0° C.(i.e. of below −10° C. or in particular of below −5° C. or specificallyof below 0° C.) or above the gelling point of the cellulose derivativeused (of course only if the respective cellulose derivative has agelling point under the given reaction conditions, especially theconcentration in which the cellulose derivative is used).

“Solvent” is a liquid substance that dissolves a solute (a chemicallydifferent liquid, solid or gas), resulting in a solution. In terms ofthe present invention, the solvent is not restricted to a compound ormedium which dissolves the reagents in the proper sense: This compoundor medium may be more generally a dispersing medium, and thus the“solution” might be a suspension, emulsion or solution in the propersense (solution in the proper sense being a homogeneous mixture composedof two or more substances, where the particles of the solute cannot beseen by naked eye and which does not scatter light).

As a matter of course, the term “solvent” in the terms of the presentinvention does not include the stoichiometric amounts of liquidreactants (i.e. those amounts theoretically needed for the reaction withrespect to the amount of the other reactant(s)) which may principallyact as a solvent for other reagent(s). By way of example, in a Heckreaction of 1 mole of chlorobenzene and 1 mole of methylacrylate,chlorobenzene may principally act as solvent for the acrylate. However,this 1 mole of chlorobenzene is not considered as belonging to thesolvent in the terms of the present invention and thus is not part ofthe 10% by weight or in particular 3% by weight of the solvent which maybe different from water. The term “solvent” in the terms of the presentinvention does moreover not include the excess amount of any liquidreactant which may principally act as a solvent for other reagent(s).For instance, if in the above example chlorobenzene is used in excess,for example here in an amount of 1.2 mole, this excess of 0.2 mole isnot considered as part of the solvent, although chlorobenzene mayprincipally act as solvent for the acrylate, and thus is not part of the10% by weight or in particular 3% by weight of the solvent which may bedifferent from water. See however the below restrictions.

The term “solvent” in the terms of the present invention doesfurthermore not include auxiliary reagents (other than reactants; i.e.reagents which do not appear in the net reaction equation) which areliquid and can principally act as solvents, such as liquid bases (e.g.liquid amines or basic N-heterocycles, e.g. triethylamine, pyridine orlutidine). See however the below restrictions.

If the solvent contains, apart from water, a supplementary solvent, thisis usually present because it is necessary for bringing one or morereagents into the reaction vessel, e.g. if these are oily and stick tothe container in which they are kept before being introduced into thereaction. The supplementary solvent is generally chosen for its propertyto bring the reagent(s) into the reaction vessel and of course for beinginert in the reaction mixture, i.e. for not interfering with the desiredreaction. Generally, water miscible solvents which do not interfere withthe reaction are preferred. Examples are protic solvents, such asC₁-C₃-alkanols, e.g. methanol, ethanol, propanol or isopropanol, orglycols, such as ethylene glycol, diethylene glycol, triethylene glycolor polyethyleneglycol, and polar aprotic solvents, such asN,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA),dimethylsulfoxide (DMSO), tetrahydrofuran (THF), 1,4-dioxane, acetone,methylethylketone or acetonitrile. If these polar solvents are howevernot useful for the intended purpose, i.e. for bringing the reagents intothe reaction vessel, less polar solvents can be used, too.

In some very few instances the presence of a supplementary solvent mightbe useful for improving the yield of the reaction. In such cases thesolvent can be selected from any solvent type useful for the specificsurface.

These supplementary solvents are of course used in such an amount thattheir amount does not exceed 10% by weight, preferably does not exceed3% by weight, of the total weight solvent (composed of water andoptionally said supplementary solvent).

The term “solvent” in the terms of the present invention is thusrestricted to water and optionally another solvent which is inert in thereaction and generally has no other role but to bring one or morereagents into the reaction vessel.

In particular, the amount of optionally present excess liquid reactantsuitable to act as solvent for the other reagent(s) plus the amount ofoptionally present liquid auxiliary reagent(s) plus the amount ofoptionally present supplementary solvent does not exceed 35% by weight,preferably does not exceed 30% by weight, in particular does not exceed25% by weight, more particularly does not exceed 20% by weight,specifically does not exceed 15% by weight, very specifically does notexceed 10% by weight, more specifically does not exceed 8% by weight, ofthe total weight of water plus excess liquid reactant suitable to act assolvent for the other reagent(s) plus liquid auxiliary reagent(s) plussupplementary solvent.

In terms of the present invention, “cellulose modified with one or morealkylene oxides or other hydroxyalkyl precursors” relates tohydroxyalkylcelluloses; i.e. to celluloses in which a part of thehydrogen atoms of the OH groups is replaced by hydroxyalkyl groups. Inthese hydroxyalkylcelluloses another part of the hydrogen atoms of theOH groups may be replaced by alkyl groups. Such derivatives are termedhydroxyalkyl(alkyl)celluloses.

The term “alkylcellulose” relates to celluloses in which a part of thehydrogen atoms of the OH groups are replaced by alkyl groups. In termsof the present invention, in alkylcelluloses, hydrogen atoms of the OHgroups are not replaced by hydroxyalkyl groups.

The term “reagents” means starting compounds (also termed startingmaterials or reactants), and also catalysts, catalyst ligands, couplingagents and other compounds which do not appear in the net reactionequation. The cellulose derivative is however not considered as areagent. Generally, the solvent is not considered a reagent, either,except in cases where it is consumed, such as water in a hydrolyzationreaction.

The term “starting compound” or “starting material” or “reactant”relates to those substances which are consumed in the course of achemical reaction and which are indispensable yet for the “paper” or netreaction (e.g. alcohol and acid or acid derivative for anesterification, amine and acid or acid derivative for an amidesynthesis, diene and dienophile for a Diels-Alder reaction, organoboroncompound and halide or sulfonate compound for a Suzuki reaction, etc.).Thus, catalysts, catalyst ligands, coupling agents and the like are no“starting compounds” or “starting materials” or “reactants” in the termsof the present invention.

The method of the invention is suitable for reactions in which all thereagents are water-miscible or water-soluble under the given reactionconditions (e.g. reaction temperature, degree of dilution of thereagents, etc.); its advantages become however especially manifest inreactions in which at least one of the reagents is not or only scarcelywater-soluble or water-miscible. “Miscible” generally refers to twoliquids; thus the term water miscibility relates to liquid reagents.“Soluble” generally refers to a property of a gas or a solid in aliquid; thus the term water-solubility relates to gaseous or solidreagents. In the present invention, however, the term “water solubility”is used indiscriminately both for water miscibility and solubility, andthus independently of the physical state of the reagent(s).

In one embodiment, at least one of the reagents has a water solubilityof at most 100 g per 1 l of water, in particular at most 50 g per 1 l ofwater, more particularly at most 10 g per 1 l of water, and specificallyat most 5 g per 1 l of water at 20° C.+/−20% and 101325 Pascal+/−20%. Inanother embodiment, at least one of the starting compounds has a watersolubility of at most 100 g per 1 l of water, in particular at most 50 gper 1 l of water, more particularly at most 10 g per 1 l of water, andspecifically at most 5 g per 1 l of water at 20° C.+/−20% and 101325Pascal+/−20%.

Cellulose Derivative

Without wishing to be bound by theory, it is assumed that the cellulosederivatives form in the aqueous medium a three-dimensional hollowstructure inside which or at the interface (phase boundary) of which atleast a part of the organic reaction takes place.

As said above, “cellulose modified with one or more alkylene oxides orother hydroxyalkyl precursors” relates to hydroxyalkylcelluloses; i.e.to celluloses in which a part of the hydrogen atoms of the OH groups isreplaced by a hydroxyalkyl group, in particular by a C₂-C₄-hydroxyalkylgroup, especially by a C₂-C₃-hydroxyalkyl group. Suitable alkyleneoxides for modifying celluloses are ethylene oxide and 1,2-propyleneoxide. Other hydroxyalkyl precursors are for example tetrahydrofuran.Preferably, ethylene oxide and/or 1,2-propylene oxide and especially1,2-propylene oxide are used for modifying cellulose, and thus thecellulose modified with one or more alkylene oxides or otherhydroxyalkyl precursors is preferably a hydroxyethylcellulose, a2-hydroxypropylcellulose or a mixedhydroxyethyl-2-hydroxypropylcellulose; i.e. a cellulose in which a partof the hydrogen atoms of the OH groups is replaced by hydroxyethyl-and/or 2-hydroxypropyl groups.

In these hydroxyalkylcelluloses another part of the hydrogen atoms ofthe OH groups may be replaced by alkyl groups, especially by C₁-C₃-alkylgroups, such as methyl, ethyl or propyl groups, especially by methyl orethyl groups. Such derivatives are termed“hydroxyalkyl(alkyl)celluloses”. Derivatives in which another part ofthe hydrogen atoms of the OH groups is indeed replaced by alkyl groupsare termed “hydroxyalkylalkylcelluloses”.

The term “alkylcellulose” relates to celluloses in which a part of thehydrogen atoms of the OH groups are replaced by alkyl groups, especiallyby C₁-C₃-alkyl groups, such as methyl, ethyl or propyl groups,especially by methyl groups. In terms of the present invention, in orderto distinguish them from hydroxyalkylalkylcelluloses, inalkylcelluloses, hydrogen atoms of the OH groups are not replaced byhydroxyalkyl groups.

Alkylcelluloses can be prepared by reacting cellulose, generally after apretreatment with a base, with an alkylation agent, such as a methyl,ethyl or propyl halide, e.g. methyl chloride, bromide or iodide,dimethyl sulfate, ethyl chloride, bromide or iodide, diethyl sulfate andthe like.

Hydroxyalkylcelluloses can be prepared by reacting cellulose, generallyafter a pretreatment with a base, with an alkylene oxide, such asethylene oxide or 1,2-propylene oxide, or with another hydroxyalkylprecursors, such as tetrahydrofuran.

Hydroxyalkylalkylcelluloses can be prepared by reacting alkylcelluloses,generally after a pretreatment with a base, with an alkylene oxide, suchas ethylene oxide or 1,2-propylene oxide, or with another hydroxyalkylprecursors, such as tetrahydrofuran, or by reacting cellulose, alsogenerally after a pretreatment with a base, with an alkylene oxide, suchas ethylene oxide or 1,2-propylene oxide, or with another hydroxyalkylprecursors, such as tetrahydrofuran, and simultaneously with analkylation agent, such as a methyl, ethyl or propyl halide, e.g. methylchloride, bromide or iodide, dimethyl sulfate, ethyl chloride, bromideor iodide, diethyl sulfate and the like.

Under the reaction conditions alkylene oxides or other hydroxyalkylprecursors might react with hydroxyalkyl groups already bound to thecelluloses, thus yielding oligoether groups terminated by OH. Suchcompounds are also enclosed in the present cellulose derivatives, moreprecisely in the terms “hydroxyalkylcelluloses”,“hydroxyalkyl(alkyl)celluloses” and “hydroxyalkylalkylcelluloses”.

The cellulose derivatives may also be used in quaternized form; i.e. maycontain an ammonium or (di/tri)alkylammonium group. Such ammonium groupsmay for example be introduced by reacting a hydroxyl group of thecellulose derivative with an epoxide containing an ammonium group or anamino group which is then quaternized via alkylation.

Cellulose derivatives are generally characterized by their size and thedegree of substitution. The cellulose derivatives are generallymacromolecules, and thus their size or weight has to be determined bymethods suitable for characterizing polymers. Generally, cellulosederivatives are characterized by their viscosity. Viscosity can bedetermined by various methods, for example with a Brookfield LV or RV,Höppler falling ball, Haake Rotovisco, and the like. If not indicatedotherwise, in the present invention, viscosity values of up to (andincluding) 70 mPa·s are values obtained with a 2% by weight solution ofthe cellulose derivative in water, relative to the weight of water, at25° C., as determined when using a Malvern Instruments Viscosizer 200and an uncoated glass capillary (Art.-Nr. PRY2007, Malvern Instruments)and applying following protocol:

Pressure Duration Step Solution (mBar) (min) wash 3% Mucasol ™ 2000 1universal detergent rinse water 2000 4 fill water 2000 1 reset baselinewater 1000 1 load sample sample 1000 auto dip (clean inlet) water 0  0.15 ran water 1000 autoA 1 mg/mL caffeine in water solution is used as viscosity reference at0.8905 mPa·s. Raw data is fitted using the trailing region of thedetector trace with a sampling interval of 55 and peak region thresholdof 30%.

If not indicated otherwise, in the present invention, viscosities ofabove 70 mPa·s and up to (and including) 4000 mPa·s are values obtainedwith a 2% by weight solution of the cellulose derivative in water,relative to the weight of water, at 25° C., as determined when using afalling-sphere viscosimeter: First, sample density is determined with anAnton Paar DMA 4100 densitometer. Sample density is used to determinedynamic viscosity with an Anton Paar AMVn viscosimeter equipped with an1.8 mm capillary or an Anton Paar Lovis 2000 ME viscosimeter equippedwith a 2.5 mm capillary. Measurements are performed as quadruplicates at25° C. with capillaries tilted to 70°.

If not indicated otherwise, in the present invention, viscosities ofabove 4000 mPa·s are values obtained with a 2% by weight solution of thecellulose derivative in water, relative to the weight of water, at 20°C., as described in European Pharmacopoeia 8.6, 01/2016:0348, Chapter“Hypromellose”, Method 2, using a single-cylinder type spindleviscosimeter. For viscosities below 9500 mPa·s, following specificationsapply: rotor number: 4; revolutions. 60 r/min; calculation multiplier:100; for viscosities of from 9500 to <99500 mPa·s, followingspecifications apply: rotor number 4; revolutions. 6 r/min; calculationmultiplier: 1000; and for viscosities of 99500 mPa·s and above,following specifications apply: rotor number: 4; revolutions. 3 r/min;calculation multiplier: 2000.

In a preferred embodiment, the cellulose derivative has a viscosity offrom 1 to 150000 mPa·s, more preferably 2 to 100000 mPa·s, in particular2 to 10000 mPa·s, more particularly 2 to 6000 mPa·s, even moreparticularly 2 to 1000 mPa·s, specifically 2 to 100 mPa·s, morespecifically 2 to 80 mPa·s, very specifically 3 to 70 mPa·s, determinedas a 2% by weight aqueous solution, relative to the weight of water, atthe temperature and with the method as described above (viscosities of 1to 70 mPa·s determined at 25° C. with a Malvern Instruments Viscosizer200 according to the above-described method; viscosities of >70 to 4000mPa·s determined at 25° C. with a falling-sphere viscosimeter accordingto the above-described method; viscosities of >4000 mPa·s determined at20° C. with a single-cylinder type spindle viscosimeter according to theabove-described method (in the case of viscosities of >4000 mPa·s asgiven by the respective suppliers). In a specific embodiment, thecellulose derivative has a viscosity of from 2 to 7 mPa·s, specificallyfrom 3 to 6 mPa·s, very specifically from 3.5 to 6 mPa·s or from 3.8 to5 mPa·s, determined as a 2% by weight aqueous solution, relative to theweight of water, at 25° C. with a Malvern Instruments Viscosizer 200according to the above-described method. In another specific embodiment,the cellulose derivative has a viscosity of from 10 to 20 mPa·s,determined as a 2% by weight aqueous solution, relative to the weight ofwater, at 25° C. with a Malvern Instruments Viscosizer 200 according tothe above-described method. In another specific embodiment, thecellulose derivative has a viscosity of from 30 to 70 mPa·s,specifically from 40 to 60 mPa·s, very specifically from 40 to 50 mPa·s,determined as a 2% by weight aqueous solution, relative to the weight ofwater, at 25° C. with a Malvern Instruments Viscosizer 200 according tothe above-described method. In another specific embodiment, thecellulose derivative has a viscosity of from 70 to 150 mPa·s,specifically from 75 to 120 or 75 to 100 mPa·s, determined as a 2% byweight aqueous solution, relative to the weight of water, at 25° C. witha falling-sphere viscosimeter according to the above-described method.In another specific embodiment, the cellulose derivative has a viscosityof from 100 to 600 mPa·s, specifically from 100 to 500 mPa·s, determinedas a 2% by weight aqueous solution, relative to the weight of water, at25° C. with a falling-sphere viscosimeter according to theabove-described method. In another specific embodiment, the cellulosederivative has a viscosity of from 2000 to 6000 mPa·s, specifically from2500 to 5700 mPa·s, very specifically from 3000 to 4000 mPa·s,determined at 20° C. with a single-cylinder type spindle viscosimeteraccording to the above-described method. 1 mPa·s is 1 cP (cP=centipoise;also abbreviated as cps).

In an alternatively preferred embodiment, the cellulose derivative has amolecular weight of from 5000 to 1500000, more preferably from 6000 to1000000, in particular from 7000 to 500000, more particularly from 8000to 250000, even more particularly from 8000 to 100000, specifically from8000 to 50000 Dalton. The molecular weight values relate to the weightaverage molecular weight.

The degree of substitution is the average level of alkyl and/orhydroxyalkyl substitution on the cellulose chain. The degree ofsubstitution is often expressed in percentages.

In a preferred embodiment, in the cellulose derivative 5 to 70%, inparticular 10 to 60%, specifically 15 to 50%, more specifically 20 to45%, very specifically 25 to 45% of the hydrogen atoms in the hydroxylgroups of the cellulose on which the cellulose derivative is based arereplaced by a hydroxyalkyl and/or alkyl group.

In particular, the cellulose derivative is selected from the groupconsisting of hydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxyethylmethylcellulose, ethylhydroxyethylcellulose,hydroxyethylcellulose and methylcellulose, and especially fromhydroxypropylmethylcellulose, hydroxyethylcellulose, andmethylcellulose. Particularly, however, the cellulose derivative is ahydroxyalkylcellulose. Thus, more particularly, the cellulose derivativeis selected from the group consisting of hydroxypropylmethylcellulose,hydroxypropylcellulose, hydroxyethylmethylcellulose,ethylhydroxyethylcellulose and hydroxyethylcellulose and especially fromhydroxypropylmethylcellulose and hydroxyethylcellulose.

Specifically, the cellulose derivative is hydroxypropylmethylcellulose.

Various viscosities and substitution degrees of the abovehydroxyalkyl(alkyl)-celluloses and alkylcelluloses are commerciallyavailable.

In a preferred embodiment, the cellulose derivative is used in an amountof from 0.01 to 15% by weight, in particular 0.05 to 10% by weight, moreparticularly 0.1 to 7% by weight, specifically 0.2 to 5% by weight,based on the weight of the solvent.

In another preferred embodiment, the cellulose derivative is used in anamount of from 0.01 to 15% by weight, in particular 0.05 to 10% byweight, more particularly 0.1 to 7% by weight, specifically 0.2 to 5% byweight, based on the weight of water (water being the only solvent ormaking up at least 90% by weight of the solvent, in particular at least97% by weight of the solvent, the percentages being based on the totalweight of the solvent).

In a preferred embodiment, the weight ratio of the cellulose derivativeand all reagents is of from 1:1 to 1:200, in particular 1:1 to 1:100,more particularly 1:2 to 1:70, specifically 1:5 to 1:60. The term“reagents” is as defined above, i.e. it includes catalysts, catalystligands, coupling agents and other compounds which do not appear in thenet reaction equation.

In a preferred embodiment, the weight ratio of the cellulose derivativeand the starting compounds, i.e. those compounds indispensable for therespective reaction (e.g. alcohol and acid or acid derivative for anesterification, amine and acid or acid derivative for an amidesynthesis, diene and dienophile for a Diels-Alder reaction, organoboroncompound and halide or sulfonate compound for a Suzuki reaction, etc.),i.e. exclusive of any catalysts, ligands therefor, coupling agents andother compounds which do not appear in the net reaction equation, is offrom 1:1 to 1:150, in particular 1:1 to 1:100, more particularly 1:2 to1:50, specifically 1:2 to 1:30.

In cases in which high dilution is not important (high dilution is forexample advantageous in intramolecular reactions, like lactone or lactamformation, in order to suppress competing intermolecular reactions), itis preferred to carry out the present organic reactions in rather highconcentration. Preferably the reaction is carried out in such a way thatthe reactant used in substoichiometric amounts is present in thereaction medium in a concentration of from 0.1 to 5 mol per l ofsolvent, more preferably from 0.2 to 4 mol per l of solvent, inparticular from 0.3 to 3 mol per l of solvent, more particularly from0.5 to 3 mol per l of solvent and specifically from 0.8 to 3 mol per lof solvent. In case that the reactants are used in equimolar amounts,the above concentrations apply of course simply to one of thesereactants. Alternatively preferably the reaction is carried out in sucha way that the overall concentration of all reagents (i.e. reactants,catalysts, ligands, coupling agents) is of from 0.2 to 10 mol per l ofsolvent, more preferably from 0.4 to 8 mol per l of solvent, inparticular from 0.8 to 6 mol per l of solvent and specifically from 1 to4 mol per l of solvent.

Reaction Temperature

As indicated above, the limiting factor of reaction temperature is onthe lower side the temperature at which the reaction mixture solidifies(0° C. or somewhat lower, e.g. −10° C. or −5° C.) and on the upper sidethe gelation point, i.e. the temperature at which the reaction mixturegels, or, if the cellulose derivative does not gel, the boiling point ofthe reaction mixture at the given pressure. Preferably the reaction iscarried out at of from 5° C. to 80° C., more preferably from 10° C. to70° C., in particular from 20° C. to 70° C., more particularly from 20°C. to 65° C. and specifically from 20° C. to 55° C., e.g. at from 20 to25° C. or at from 45 to 55° C. or at from 48 to 52° C. The reactiontemperature will be chosen according to the specific aim of the specificreaction. Higher reaction temperatures, e.g. around 50° C. to 70° C.,will generally shorten reaction times significantly, but lowertemperatures might lead to a more selective formation of the desiredproduct, which advantage may overweigh longer reaction times.

Organic Reactions

As said above, basic types of organic reactions are addition reactions,elimination reactions, substitution reactions, pericyclic reactions,rearrangement reactions, photochemical reactions and redox reactions.Thus, in one aspect, the organic reactions of the present invention areselected from the group consisting of addition reactions, eliminationreactions, substitution reactions, pericyclic reactions, rearrangementreactions, photochemical reactions and redox reactions.

Addition Reactions:

In this reaction type two or more molecules combine to form a larger one(the adduct). Addition reactions are limited to chemical compounds thathave multiple bonds, such as molecules with carbon-carbon double bonds(alkenes, alkadienes, cycloalkenes, cycloalkadienes and other olefiniccompounds) or triple bonds (alkynes, alkadiynes, cycloalkynes etc.), orwith carbon-heteroatom double bonds, like carbonyl (C═O) groups or imine(C═N) groups or carbon-heteroatom triple bonds, like cyano (C≡N).Addition can take place by initial attack of a nucleophile, anelectrophile or a free radical. Examples are the addition of hydrogenhalides, other acids, like sulfuric acid or carboxylic acids, halogens,hydrogen, water, alcohols, hydrogen sulfide, thiols, ammonia, amines,hydroazoic acid to C—C double or triple bonds, the addition of hydrogento C═O, C═N or C≡N bonds to give the reduced species, pericyclicreactions like Diels-Alder and various other cycloadditions, and manymore. See for example J. March, Advanced Organic Chemistry, 3^(rd) ed.,John Wiley & Sons, p. 657 et seq.

Elimination Reactions:

In this reaction type two substituents are removed from a molecule ineither a one or two-step mechanism. Examples are dehydration(α,β-hydro-hydroxy elimination), α,β-hydro-alkoxy elimination,α,β-hydro-halo elimination, intramolecular condensation reactions etc.Elimination in α,β-position normally leads to unsaturated compounds,e.g. olefins, alkynes or aromatic compounds. Intramolecular condensationnormally leads to a cyclic system, e.g. to a lactone or lactam.

Substitution Reactions

In substitution reactions one functional group in a chemical compound isreplaced by another functional group. Depending on the substituent type,substitution reactions are classified as nucleophilic (S_(N)),electrophilic (S_(E)) or radical (S_(R)). Examples are S_(N)1 and S_(N)2reactions of aliphatic or cycloaliphatic compounds, S_(E), S_(N)reactions on (hetero)aromatic compounds, S_(R) on aromatic compoundslike the Sandmeyer reaction, transition metal catalyzed C—C, C—O, C—N orC—S coupling reactions, etc.

Pericyclic Reactions

In pericyclic reactions the transition state of the molecule has acyclic geometry, the reaction progresses in a concerted fashion and noradical or ionic intermediates are formed. Examples are concertedcycloadditions, like Diels-Alder reaction, Paterno Büchi reactions or1,3-cycloadditons; sigmatropic rearrangements, cheletropic reactionsetc.

Rearrangement Reactions

In rearrangement reactions, the carbon skeleton of a molecule isrearranged to give a structural isomer of the original molecule. Often asubstituent moves from one atom to another atom in the same molecule.

Photochemical Reactions

In photochemical reactions, a chemical reaction is caused by absorptionof ultraviolet (wavelength from 100 to 400 nm), visible light (400-750nm) or infrared radiation (750-2500 nm). Examples are [2+2] and otherthermally forbidden cycloadditions, di-pi-methane rearrangement, Norrishtype I and II reactions, photoredox reactions etc.

Redox Reactions

Redox reactions encompass oxidations and reductions.

As many reactions cannot be categorized to belong to only one of theabove types, in the following other categories will be used.

Thus, the organic reactions of the present invention are in particularselected from the group consisting of

-   -   transition metal catalyzed reactions, especially transition        metal catalyzed C—C coupling reactions, and transition metal        catalyzed reactions involving C—N, C—O, C—S, C—B or C-halogen        bond formation,    -   C—C coupling reactions not requiring transition metal catalysis,        such as the Wittig reaction, pericyclic reactions like the        Diels-Alder reaction or photochemically induced reactions like        [2+2] cycloaddition or cyclopropanation reactions, or reaction        of carbonyl compounds with CH acidic compounds, such as in the        aldol reaction or the Knoevenagel reaction or Michael addition        and the like,    -   reactions involving C—N bond formation and not requiring        transition metal catalysis, such as carboxamide bond formation        (amidation; synthesis of amides/peptides), urea formation,        carbamate formation (formation of C(O)—N bond in the carbamate),        amination (in the sense of nucleophilic substitution), reductive        amination, Michael addition with N nucleophiles or nitration,    -   reactions involving C—O bond formation and not requiring        transition metal catalysis, such as esterification or        etherification or carbamate formation (formation of C(O)—O bond        in the carbamate) or Michael addition with O nucleophiles,    -   reactions involving C-halogen bond formation and not requiring        transition metal catalysis, such as halogenation of e.g.        aromatic compounds,    -   reactions involving S—N bond formation and not requiring        transition metal catalysis, such as sulfonamide bond formation        (synthesis of sulfonamides) or Michael addition with S        nucleophiles,    -   substitution reactions, such as (cyclo)aliphatic nucleophilic        substitution, aromatic nucleophilic, electrophilic or radical        substitution,    -   reductions and oxidations (redox reactions),    -   protection and deprotection reactions,    -   photochemically induced reactions, and    -   combined forms of the above reaction types.

The method of the invention also allows to carry out a chain ofdifferent organic reactions as a one pot reaction, such as protection ofa functional group, reaction at another functional group, deprotectionand, where expedient, further reaction of the deprotected functionalgroup.

Transition Metal-Catalyzed Reactions

In one particular embodiment of the invention, in the organic reaction atransition metal catalyst is used; i.e. the organic reaction is atransition metal-catalyzed reaction.

Transition metal-catalyzed reactions are all organic reactions whichinvolve the use of one or more transition metals as catalysts.Typically, they result in C—C, C—N, C—O, C—S, C—B or C-halogen bondformation. C—C bond formation is also called coupling reaction. If thetwo substrates to be coupled are different, the coupling reaction istermed cross coupling, while in case of identical substrates it istermed homocoupling.

Most transition metals are useful as catalysts; however, due to theiravailability and acceptable toxicity, the following metals are mostlyused: Fe, Ru, Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, Au, and Zn. Thus, in apreferred embodiment, the transition metal is selected from the groupconsisting of Fe, Ru, Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, Au, and Zn. Inparticular, the transition metal is selected from the group consistingof Ru, Rh, Ni, Pd, Pt, Cu and Au. In another particular embodiment, thetransition metal is Fe.

Transition metals can be used with an oxidation state of 0 or inoxidized form. In an oxidation state of 0, the transition metals aregenerally used as complexes to make their homogeneous distribution inthe reaction medium possible. Alternatively they can be used as such(i.e. in elementary form), advantageously in a finely divided form, orsupported on a carrier, to act as a heterogeneous catalyst. In oxidizedform, the transition metals can be used in form of their salts, oxidesor, mostly, in form of their complexes. The transition metal catalystscan also be used in form of their precursors, i.e. the active form formsin situ. For instance, in reactions requiring the metal in an oxidationstate of 0 the transition metal can be introduced into the reaction inoxidized form and be reduced before or in the course of the reaction bya reduction agent present in the reaction.

In a particular embodiment, the transition metal catalyst is not acatalyst supported on a cellulose derivative or on cellulose.

In another particular embodiment the catalyst is used as a catalystcomplex. Suitable complex ligands are well known and often containphosphorus. Examples for phosphorus ligands aredi-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP;Mo-Phos), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (t-BuXPhos, tBuXPhos, tert-Butyl XPhos), 1,1′-bis(diphenylphosphino)ferrocene(dppf), 1,1′-bis(di-tert-butylphosphino)ferrocene (dtbpf),1,2-bis(diphenylphosphino)ethane (dppe),1,3-bis(diphenylphosphino)propane (dppp),1,4-bis(diphenylphosphino)butane (dppb),(2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane(diop), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) (Amphos),(2S,3S)-(−)-bis(diphenylphosphino)butane (Chiraphos),di-(tert-butyl)phenylphosphine,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP),[1,1′-biphenyl]-2-diisopropyl phosphine,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos),4,5-bis-(di-1-(3-methylindolyl)-phosphoramidit)-2,7,9,9-tetramethylxanthene(MeSkatOX), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-phos),2-(2-dicyclohexyl-phosphanylphenyl)-N1,N1,N3,N3-tetramethyl-benzene-1,3-diamine(C-phos),6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphine,[(4R)-(4,4′-bis-1,3-benzodioxole)-5,5′-diyl]bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphine]((R)-DTBM-SEGPHOS®),(R)- or (S)-3,5-Xyl-MeO-BIPHEP, (R,S)- or (S,R)-PPF-P(t-Bu)₂, theJosiphos ligands, triphenylphosphite,tri-(2-(1,1-dimethylethyl)-4-methoxy-phenyl)-phosphite,tricyclohexylphosphine, tri(tert-butyl)phosphine,butyldi-1-adamantylphosphine (cataCXium),1,6-bis(diphenylphosphino)hexane (DPPH),2,6-bis(2,5-dimethylphenyl)-1-octyl-4-phenylphosphacyclohexan (PCH),tris(3-sulfophenyl)phosphine trisodium salt (TPPTS) and the like.

Non-phosphorus ligands are for example bis(dibenzylideneacetone) (dba),acetonitrile, bisoxazoline and the like. Further, Pd catalysts withnon-phosphorus ligands are for example the PEPPSI catalysts(PEPPSI=Pyridine-Enhanced Precatalyst Preparation Stabilization andInitiation)

in which R is a small organic fragment, e.g. methyl, ethyl, isopropyl,isopentyl, or isoheptyl. The corresponding catalysts are labeled asPEPPSI-IMes, PEPPSI-IEt, PEPPSI-IPr, PEPPSI-IPent, and PEPPSI-IHeptrespectively, with or without “Pd-” added in front.

Also new generation PEPPSI catalysts are suitable:

Here, too, R is a small organic fragment, e.g. methyl, ethyl, isopropyl,isopentyl, or isoheptyl.

Other suitable non-phosphorus ligands are for example porphyrins, suchas shown in the following formula. They are mostly used with Fe, Ru, Rhor Ir as central metal, but Zn may also be used.

Generally, at least one of R^(a), R^(b), R^(c) and R^(d) is an aromaticgroup, such as phenyl, optionally substituted by 1, 2 or 3 substituentsselected from the group consisting of methyl, methoxy, hydroxyl, amino,alkylcarbonyl, alkoxycarbonyl and the like. For sterically selectivereactions, expediently, at least one of R^(a), R^(b), R^(c) and R^(d) isa chiral group, such as a BINAP radical, a phenyl ring carrying one ormore chiral substituents or a phenyl ring fused to one or more ringsresulting in a chiral system. Radicals R^(a), R^(b), R^(c) and R^(d)which are not an aromatic group are generally selected from the groupconsisting of alkyl groups, alkoxy groups, alkyl carbonyl groups andalkoxycarbonyl groups. They can however also be hydrogen.

Transition metal complexes of these porphyrin ligands, in particularcomplexes with Fe, Ru, Rh or Ir as central metal, are especially usefulin cyclopropanation reactions.

Other suitable ligands are the following semicorrin or bis-oxazolin (BOXand PyBOX) ligands:

R can have various meanings, such as C₁-C₄-alkyl, C₁-C₄-alkylsubstituted by OH, tri-C₁-C₄-alkyl-silyloxy, C₁-C₄-alkylcarbonyl,C₁-C₄-alkoxycarbonyl or phenyl; C₁-C₄-alkylcarbonyl,C₁-C₄-alkoxycarbonyl or phenyl. Each R′ is generally independently H orC₁-C₄-alkyl, in particular H or methyl.

These ligands are generally used with Cu as central metal. Coppercomplexes of these ligands are especially useful in cyclopropanationreactions.

a) C—C Coupling Reactions

In a particular embodiment, the transition metal catalyzed reaction is aC—C coupling reaction. Transition metal catalyzed C—C coupling reactionsare well known, and are often named reactions. Examples are theSuzuki-Miyaura reaction (or Suzuki-Miyaura coupling or just Suzukireaction or just Suzuki coupling), Negishi coupling, Heck reaction, C—Ccoupling reactions involving C—H activation (different from Heckreaction), Sonogashira coupling, Stille coupling, Grubbs olefinmetathesis, 1,4-additions of organoborane compounds to α,β-olefinicallyunsaturated carbonyl compounds, in particular Rh-catalyzed1,4-additions, Kumada coupling, Hiyama coupling, Ullmann reaction,Glaser coupling (inclusive the Eglinton and the Hay coupling),Cadiot-Chodkiewicz coupling, the Fukuyama coupling, hydroformylations orcyclopropanations.

The Suzuki reaction is a cross coupling reaction in which an organoboroncompound is reacted with an organic halogenide or sulfonate [thesulfonate being in particular a fluorinated alkylsulfonate or tosylate,specifically triflate (trifluoromethylsulfonate) or nonaflate(nonafluorobutylsulfonate)], e.g. with an alkyl, alkenyl, alkynyl, arylor heteroaryl halogenide or sulfonate (the sulfonate being in particulara fluorinated alkylsulfonate or tosylate, specifically triflate ornonaflate), in the presence of a transition metal catalyst, mostly a Pdor Ni catalyst, and in general also of a base.

The Negishi reaction is a cross coupling reaction in which an organozinccompound is reacted with an organic halogenide or sulfonate (thesulfonate being in particular a fluorinated alkylsulfonate or tosylate,specifically triflate or nonaflate), e.g. with an alkyl, alkenyl,alkynyl, aryl or heteroaryl halogenide or sulfonate (the sulfonate beingin particular a fluorinated alkylsulfonate or tosylate, specificallytriflate or nonaflate), in the presence of a transition metal catalyst,mostly a Pd or Ni catalyst. Organoaluminum or organozirconium compoundscan be used instead of the organozinc compound.

In Heck reactions an aryl, heteroaryl, benzyl, vinyl or alkyl halogenideor sulfonate (the sulfonate being in particular a fluorinatedalkylsulfonate or tosylate, specifically triflate, nonaflate ortosylate) (the alkyl group must not contain any β-hydrogen atoms) isreacted with an olefinically unsaturated compound in the presence of atransition metal catalyst, mostly a Pd catalyst, and generally also inthe presence of a base.

C—C coupling reactions involving C—H activation are coupling reactionsin which one of the reactants reacts via a C—H bond and not via aspecific activating group. The Heck reaction is such a reactioninvolving C—H activation. In the present case, in the C—C couplingreactions involving C—H activation two aromatic or heteroaromaticcompounds are coupled.

The Sonogashira reaction is a cross coupling reaction in which an aryl,heteroaryl or vinyl halogenide or sulfonate (the sulfonate being inparticular a fluorinated alkylsulfonate or tosylate, specificallytriflate or nonaflate) is reacted with a terminal alkyne in the presenceof a transition metal catalyst, mostly a Pd catalyst, generally also ofa base and optionally of a Cu(I) salt (also in catalytic amounts).

The Stille reaction, also termed Migita-Kosugi-Stille coupling, is across coupling reaction in which an organotin compound (organostannane)is reacted with an alkenyl, aryl, heteroaryl or acyl halide, sulfonate(the sulfonate being in particular a fluorinated alkylsulfonate ortosylate, specifically triflate or nonaflate) or phosphate in thepresence of a Pd catalyst.

Grubbs olefin metathesis is an olefin metathesis in which a Grubbscatalyst is used. An olefin metathesis is an organic reaction thatentails the redistribution of fragments of alkenes (olefins) by thescission and regeneration of carbon-carbon double bonds. Grubbscatalysts are Ruthenium carbene complexes. For further details seebelow.

Rh-catalyzed 1,4-additions in the terms of the present invention are 1,4additions of organoborane compounds, in particular of aryl or heteroarylboronic acids, to α,β-olefinically unsaturated carbonyl compounds, inparticular to α,β-unsaturated carboxylic acids or acid derivatives, inthe presence of a rhodium catalyst to give 3-(het)arylpropionic acids oracid derivatives. However, Pd and Ru catalysts are principally alsosuitable for such 1,4 additions of organoborane compounds toα,β-olefinically unsaturated carbonyl compounds.

The Kumada reaction is a cross coupling reaction in which a vinyl halideor sulfonate (the sulfonate being in particular a fluorinatedalkylsulfonate or tosylate, specifically triflate or nonaflate) isreacted with a Grignard reagent or a lithium organyl in the presence ofa transition metal catalyst, mostly a Pd or Ni catalyst.

The Hiyama reaction is cross-coupling reaction in which an aryl,heteroaryl, alkenyl or alkynyl silane is reacted with an organic halideor sulfonate (the sulfonate being in particular a fluorinatedalkylsulfonate or tosylate, specifically triflate or nonaflate), e.g. analkyl, alkenyl, alkynyl, aryl or heteroaryl halide or sulfonate (thesulfonate being in particular a fluorinated alkylsulfonate or tosylate,specifically triflate or nonaflate), in the presence of a transitionmetal catalyst, mostly a Pd catalyst.

The Ullmann reaction or Ullmann coupling is a cross coupling orhomocoupling reaction in which two aryl or heteroaryl halides orpseudohalogenides (e.g. —SCN) are reacted to biaryl compounds in thepresence of copper, a Cu(I) salt or a Ni catalyst.

The Glaser coupling is homocoupling reaction in which a terminal alkyneis treated with a copper(I) salt and oxidized to give a symmetricalconjugated diyne. The original Glaser reaction was carried out inaqueous ammonia, and air or oxygen was used as oxidation agent, but interms of the present invention the Glaser coupling comprises allvariants of Cu-catalyzed homocoupling of terminal alkynes, e.g. the useof CuCl₂ or K₃Fe(CN)₆ as oxidizing agents, the Eglinton variant(Eglinton coupling), in which Cu(II) acetate and methanolic pyridine isused, or the Hay variant (Hay coupling), in which tertiary amines, likepyridine, or TMEDA are used as complexing agents for the Cu(I) salt, andair or oxygen is used as oxidizing agent.

The Cadiot-Chodkiewicz coupling is a cross coupling in which a terminalalkyne and an 1-bromoalkyne are reacted in the presence of a Cu(I)catalyst and an aliphatic amine.

The Fukuyama coupling is a cross coupling reaction in which a thioesterand an organozinc halide are reacted in the presence of a transitionmetal catalyst, mostly a Pd catalyst, to give a ketone.

In a transition metal catalyzed cyclopropanation an olefinicallyunsaturated compound is reacted with a diazo compound to a cyclopropanein the presence of a transition metal catalyst. The reaction is formallya [1+2] ring forming reaction of a carbene (formed after N₂ elimination)and an olefin; therefore cyclopropanations are herein formallyconsidered as a pericyclic reaction.

In a hydroformylation, also known as oxo synthesis or oxo process,formally a formyl group (CHO) and a hydrogen atom add to a carbon-carbondouble bond, thus giving an aldehyde. The reaction is generallycatalyzed by a Rh or Ru catalyst, mostly by a homogeneous Rh or Rucatalyst.

Particularly, the transition metal catalyzed C—C coupling reaction isselected from the group consisting of the Suzuki-Miyaura reaction (orjust Suzuki reaction), Negishi coupling, Heck reaction, C—C couplingreactions involving C—H activation other than Heck reaction (see aboveand below definition), Sonogashira coupling, Stille coupling, Grubbsolefin metathesis, 1,4-additions of organoborane compounds toα,β-olefinically unsaturated carbonyl compounds, in particularRh-catalyzed 1,4-additions, hydroformylations and cyclopropanations.Specifically, the transition metal catalyzed C—C coupling reaction isselected from the group consisting of the Suzuki-Miyaura reaction (orjust Suzuki reaction), Heck reaction, C—C coupling reactions involvingC—H activation other than Heck reaction, Sonogashira coupling, Stillecoupling, Grubbs olefin metathesis, Rh-catalyzed 1,4-additions andcyclopropanations. In another specific embodiment the transition metalcatalyzed C—C coupling reaction is selected from the group consisting ofthe Suzuki-Miyaura reaction (or just Suzuki reaction), Heck reaction,C—C coupling reactions involving C—H activation other than Heckreaction, Sonogashira coupling, Stille coupling, Grubbs olefinmetathesis and Rh-catalyzed 1,4-additions.

Suzuki-Miyaura Reaction

In a particular embodiment the transition metal catalyzed C—C couplingreaction is a Suzuki-Miyaura reaction. As said, in Suzuki reactions anorganoboron compound is reacted with an organic halogenide or sulfonate(the sulfonate being in particular a fluorinated alkylsulfonate ortosylate, specifically triflate or nonaflate), in particular with ahalogenide or sulfonate (the sulfonate being in particular a fluorinatedalkylsulfonate or tosylate, specifically triflate or nonaflate)R²—(Z)_(n), where R² is an alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl orheteroaryl group, Z is a halogenide or sulfonate (the sulfonate being inparticular a fluorinated alkylsulfonate or tosylate, specificallytriflate or nonaflate) group, especially Cl, Br, I, triflate ornonaflate, and n is 1, 2, 3 or 4, in the presence of a transition metalcatalyst, mostly a Pd or Ni catalyst, and in general also of a base.

Preferably, the organoboron compound is a compound of formula R¹—BY₂,where R¹ is an alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl,mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl group andY is an alkyl, O-alkyl or hydroxyl group, or the two substituents Y formtogether with the boron atom they are bound to a mono-, bi- orpolycyclic ring; or the organoboron compound is a compound of formulaR¹—BF₃M, where M is a metal equivalent. The reaction of the organoboroncompound with R²—(Z)_(n) yields a compound (R¹)_(n)—R². Examples ofsuitable organoboron compounds R¹—BY₂ are R¹—B(OH)₂,R¹—B(O—C₁-C₄-alkyl)₂, R¹—B(C₁-C₄-alkyl)₂, or the MIDA ester of R¹—B(OH)₂(MIDA=N-methyliminodiacetic acid; HO—C(═O)—CH₂—N(CH)—CH₂—C(═O)—OH; i.e.the two Y form together —O—C(═O)—CH₂—N(CH₃)—CH₂—C(═O)—O—). The alkyl,alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, aryl or heteroaryl halide or sulfonate can contain morethan one halide or sulfonate group (when n is 2, 3 or 4), so thatmultiply coupled compounds can form, especially if the organoboroncompound is used in excess. For instance, a difunctional compoundR²—(Z)₂ can yield a twofold coupled compound R¹—R²—R¹. In case that n is2, 3 or 4 and the reaction is intended to couple 2, 3 or 4 organicradicals deriving from the organoboron compound (e.g. 2, 3 or 4 R¹deriving from R¹—BY₂), Z in (Z)_(n) is preferably always the same; i.e.all groups Z in R²—(Z)_(n) have the same meaning.

Due to the tolerance of the Suzuki reaction to a wide variety offunctional groups, the alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl orheteroaryl groups R¹ and R² can carry one or more substituents, e.g.halogen (provided that this not more reactive than the halogen atom orsulfonate group on the desired reaction site of the R²—(Z)_(n)compound), cyano, nitro, azido, —SCN, —SF₅, OR¹¹ (provided that this notmore reactive than the halogen atom or sulfonate group on the desiredreaction site of the R²—(Z)_(n) compound), S(O)_(m)R¹¹, NR^(12a)R^(12b),C(═O)R¹³, C(═S)R¹³, C(═NR^(12a))R¹³, —Si(R¹⁴)₃, cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, where the five last-mentioned cyclic substituents maycarry one or more substituents selected from R¹⁵; aryl which may besubstituted by one or more radicals R¹⁵; heterocyclyl which may besubstituted by one or more radicals R¹⁵; heteroaryl which may besubstituted by one or more radicals R¹⁵; oxo (═O), ═S, or ═NR^(12a);

and in case of cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl groupsR¹ and R², optional substituents on these groups can additionally bealkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl and mixedalkenyl/alkynyl, where these six radicals may in turn be substituted byone or more radicals, e.g. by halogen (provided that this not morereactive than the halogen atom or sulfonate group on the desiredreaction site of the R²—(Z)_(n) compound), cyano, nitro, azido, —SCN,—SF₅, OR¹¹, S(O)_(m)R¹¹, NR^(12a)R^(12b), C(═O)R¹³, C(═S)R¹³,C(═NR^(12a))R¹³, —Si(R¹⁴)₃, cycloalkyl, cycloalkenyl, cycloalkynyl,mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, where the fivelast-mentioned cyclic substituents may carry one or more substituentsselected from R¹⁵; aryl which may be substituted by one or more radicalsR¹⁵; heterocyclyl which may be substituted by one or more radicals R¹⁵;heteroaryl which may be substituted by one or more radicals R¹⁵; oxo(═O), ═S, and ═NR^(12a); where

-   each R¹¹ is independently selected from the group consisting of    hydrogen, cyano, alkyl, alkenyl, alkapolyenyl, alkynyl,    alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,    cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl,    where the aliphatic and cycloaliphatic moieties in the 11    last-mentioned radicals may be partially or fully halogenated and/or    may be substituted by one or more radicals R¹⁷,-    -alkyl-C(═O)OR¹⁸, -alkyl-C(═O)N(R^(12a))R^(12b),-    -alkyl-C(═S)N(R^(12a))R^(12b), -alkyl-C(═NR¹²)N(R^(12a))R^(12b),-    —Si(R¹⁴)₃, —S(O)_(m)R¹⁸, —S(O)_(m)N(R^(12a))R^(12b),    —N(R^(12a))R^(12b), —N═C(R¹⁶)₂, —C(═O)R¹³,-    —C(═O)N(R^(12a))R^(12b), —C(═S)N(R^(12a))R^(12b), —C(═O)OR¹⁸,-    aryl, optionally substituted with one or more substituents R¹⁵;-    heterocyclyl, optionally substituted with one or more substituents    R¹⁵; and-    heteroaryl, optionally substituted with one or more substituents    R¹⁵; and-   R¹¹ in the group —S(O)_(m)R¹¹ is additionally selected from the    group consisting of alkoxy and haloalkoxy;-   R¹², R^(12a) and R^(12b), independently of each other and    independently of each occurrence, are selected from the group    consisting of hydrogen, cyano, alkyl, alkenyl, alkapolyenyl,    alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl,    cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,    polycarbocyclyl, wherein the 11 last-mentioned aliphatic and    cycloaliphatic radicals may be partially or fully halogenated and/or    may be substituted by one or more, preferably 1, 2 or 3, in    particular 1, substituents R¹⁹,-    —OR²⁰, —NR^(21a)R^(21b), —S(O)_(m)R²⁰, —C(═O)N(R^(21a)R^(21b)),    —C(═O)NR²¹N(R^(21a)R^(21b)), —Si(R¹⁴)₃, —C(═O)R¹³,-    aryl which may be substituted with 1, 2, 3, 4, or 5, preferably 1,    2 or 3, in particular 1, substituents R¹⁵,-    heterocyclyl which may be substituted with one or more, preferably    1, 2 or 3, in particular 1, substituents R¹⁵; and-    heteroaryl which may be substituted with one or more, preferably 1,    2 or 3, in particular 1, substituents R¹⁵; and-    or R^(12a) and R^(12b), together with the nitrogen atom to which    they are bound, form a saturated, partially unsaturated or maximally    unsaturated heterocyclic or heteroaromatic ring, where the ring may    further contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing    groups selected from the group consisting of O, S, N, SO, SO₂, C═O    and C═S as ring members, wherein the heterocyclic or heteroaromatic    ring may be substituted with 1, 2, 3, 4 or 5, preferably 1, 2 or 3,    in particular 1, substituents independently selected from R¹⁵;-    or R^(12a) and R^(12b) together form a group ═C(R²²)₂,    ═S(O)_(m)(R²⁰)₂, ═NR^(21a) or ═NOR²⁰;-   each R¹³ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed    alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed    cycloalkenyl/cycloalkynyl, polycarbocyclyl, where the aliphatic and    cycloaliphatic moieties in the 11 last-mentioned radicals may be    partially or fully halogenated and/or may be substituted by one or    more radicals R¹⁷; aryl, optionally substituted with one or more    radicals R¹⁵; heterocyclyl, optionally substituted with one or more    radicals R¹⁵; heteroaryl, optionally substituted with one or more    radicals R¹⁵; OR²⁰, —S(O)_(m)R²⁰, —N(R^(21a))R^(21b),    —C(═O)N(R^(21a))R^(21b),-    —C(═S)N(R^(21a))R^(21b) and —C(═O)OR²⁰;-   each R¹⁴ is independently selected from the group consisting of    hydrogen, halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy,    C₁-C₆-haloalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,    C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,    C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,    C₃-C₈-halocycloalkyl, and phenyl, optionally substituted with 1, 2,    3, 4, or 5 radicals R¹⁵;-   each R¹⁵ is independently selected from the group consisting of    halogen, azido, nitro, cyano, —OH, —SH, C₁-C₆-alkoxy,    C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,    C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,    C₁-C₆-haloalkylsulfonyl, —Si(R²³)₃;-    C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, C₂-C₂₀-alkapolyenyl, C₂-C₂₀-alkynyl,    C₂-C₂₀-alkapolyynyl, mixed C₂-C₂₀-alkenyl/alkynyl, wherein the six    last-mentioned aliphatic radicals may be partially or fully    halogenated and/or may carry one or more radicals selected from the    group consisting of OH, C₁-C₂₀-alkoxy, C₁-C₂₀-haloalkoxy, SH,    C₁-C₂₀-alkylthio, C₁-C₂₀-haloalkylthio, C₁-C₂₀-alkylsulfinyl,    C₁-C₂₀-haloalkylsulfinyl, C₁-C₂₀-alkylsulfonyl,    C₁-C₂₀-haloalkylsulfonyl, —Si(R²³)₃, oxo, C₃-C₈-cycloalkyl,    C₃-C₈-cycloalkenyl, C₈-C₂₀-cycloalkynyl, mixed    C₃-C₂₀-cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl,    heterocyclyl and heteroaryl, wherein the 8 last-mentioned cyclic    radicals may in turn be partially or fully halogenated and/or may    carry one or more radicals selected from the group consisting of OH,    C₁-C₂₀-alkoxy, C₁-C₂₀-haloalkoxy, SH, C₁-C₂₀-alkylthio,    C₁-C₂₀-haloalkylthio, C₁-C₂₀-alkylsulfinyl,    C₁-C₂₀-haloalkylsulfinyl, C₁-C₂₀-alkylsulfonyl,    C₁-C₂₀-haloalkylsulfonyl, —Si(R²³)₃, oxo, C₁-C₆-alkyl,    C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl, C₂-C₆-alkynyl,    C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl,    C₈-C₂₀-cycloalkynyl, mixed C₃-C₂₀-cycloalkenyl/cycloalkynyl,    polycarbocyclyl, aryl, heterocyclyl and heteroaryl, wherein the 8    last mentioned radicals may in turn be unsubstituted, partially or    fully halogenated and/or carry 1, 2 or 3 substituents selected from    the group consisting of cyano, C₁-C₆-alkyl, C₁-C₆-haloalkyl,    C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkoxycarbonyl and    C₁-C₆-haloalkoxycarbonyl; C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl,    C₈-C₂₀-cycloalkynyl, mixed C₃-C₂₀-cycloalkenyl/cycloalkynyl,    polycarbocyclyl, wherein the 5 last-mentioned cycloaliphatic    radicals may be partially or fully halogenated and/or may carry one    or more radicals selected from the group consisting of cyano,    C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and    oxo;-    aryl, O-aryl, heterocyclyl, O-heterocyclyl, heteroaryl and    O-heteroaryl, wherein the cyclic moieties in the 6 last mentioned    radicals may be unsubstituted, partially or fully halogenated and/or    carry 1, 2 or 3, in particular 1, substituents selected from the    group consisting of C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy,    C₁-C₆-haloalkoxy, C₁-C₆-alkoxycarbonyl and C₁-C₆-haloalkoxycarbonyl;-    or-    two R¹⁵ present together on the same atom of an unsaturated or    partially unsaturated ring may be ═O, ═S, ═N(C₁-C₆-alkyl),    ═NO(C₁-C₆-alkyl), ═CH(C₁-C₄-alkyl) or ═C(C₁-C₄-alkyl)C₁-C₄-alkyl;-    or-    two R¹⁵ on two adjacent carbon or nitrogen atoms form together with    the carbon or nitrogen atoms they are bonded to a 4-, 5-, 6-, 7- or    8-membered saturated, partially unsaturated or maximally    unsaturated, including heteroaromatic, ring, wherein the ring may    contain 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from    the group consisting of N, O, S, NO, SO and SO₂, as ring members,    and wherein the ring optionally carries one or more, preferably 1, 2    or 3, in particular 1, substituents selected from the group    consisting of halogen, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl,    C₁-C₄-alkoxy and C₁-C₄-haloalkoxy;-   each R¹⁶ is independently selected from the group consisting of    hydrogen, halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,    C₂-C₆-haloalkenyl, C₂-C₆-alkynyl and C₂-C₆-haloalkynyl, wherein the    six last-mentioned aliphatic radicals may carry 1 or 2 radicals    selected from the group consisting of CN, C₃-C₄-cycloalkyl,    C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and oxo;-   each R¹⁷ is independently selected from the group consisting of    cyano, nitro, —OH, —SH, —SCN, —SF₅, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,    C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl,    C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,    C₁-C₆-haloalkylsulfonyl, —Si(R¹⁴)₃,-    C₃-C₈-cycloalkyl which may be unsubstituted, partially or fully    halogenated and/or may carry 1 or 2 radicals selected from the group    consisting of C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₈-cycloalkyl,    C₃-C₈-halocycloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and oxo;-    aryl, aryloxy, heterocyclyl, heterocyclyloxy, heteroaryl and    heteroaryloxy, where the cyclic moiety in the 6 last-mentioned    radicals may be unsubstituted, partially or fully halogenated and/or    carry 1, 2, 3, 4 or 5 substituents R¹⁵; or-    two R¹⁷ present on the same carbon atom (of an alkyl, alkenyl,    alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl,    cycloalkyl, cycloalkenyl, cycloalkynyl, mixed    cycloalkenyl/cycloalkynyl or polycarbocyclyl, group) may together be    ═O, ═CH(C₁-C₄-alkyl), ═C(C₁-C₄-alkyl)C₁-C₄-alkyl, ═N(C₁-C₆-alkyl) or    ═NO(C₁-C₆-alkyl);-    and-    R¹⁷ as a substituent on a cycloalkyl, cycloalkenyl, cycloalkynyl,    mixed cycloalkenyl/cycloalkynyl or polycarbocyclyl ring is    additionally selected from the group consisting of C₁-C₆-alkyl,    C₂-C₆-alkenyl and C₂-C₆-alkynyl, wherein the three last-mentioned    aliphatic radicals may be unsubstituted, partially or fully    halogenated and/or may carry 1 or 2 substituents selected from the    group consisting of CN, C₃-C₄-cycloalkyl, C₃-C₄-halocycloalkyl,    C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and oxo;-   each R¹⁸ is independently selected from the group consisting of    hydrogen, cyano, —Si(R¹⁴)₃,-    C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, C₂-C₂₀-alkynyl, wherein the three    last-mentioned aliphatic radicals may be unsubstituted, partially or    fully halogenated and/or may carry 1 or 2, in particular 1, radicals    selected from the group consisting of C₃-C₈-cycloalkyl,    C₃-C₈-halocycloalkyl, C₁-C₂₀-alkoxy, C₁-C₂₀-haloalkoxy,    C₁-C₂₀-alkylthio, C₁-C₂₀-haloalkylthio, C₁-C₂₀-alkylsulfinyl,    C₁-C₂₀-haloalkylsulfinyl, C₁-C₂₀-alkylsulfonyl,    C₁-C₂₀-haloalkylsulfonyl and oxo;-    C₃-C₈-cycloalkyl which may be unsubstituted, partially or fully    halogenated and/or may carry 1 or 2, in particular 1, radicals    selected from the group consisting of C₁-C₄-alkyl, C₁-C₄-haloalkyl,    C₃-C₄-cycloalkyl, C₃-C₄-halocycloalkyl, C₁-C₄-alkoxy,    C₁-C₄-haloalkoxy, C₁-C₄-alkylthio, C₁-C₄-haloalkylthio,    C₁-C₄-alkylsulfinyl, C₁-C₄-haloalkylsulfinyl, C₁-C₄-alkylsulfonyl,    C₁-C₄-haloalkylsulfonyl and oxo;-    aryl, heterocyclyl and heteroaryl, wherein the 3 last-mentioned    radicals may be unsubstituted, partially or fully halogenated and/or    carry 1, 2 or 3, preferably 1 or 2 in particular 1, substituents    selected from the group consisting of C₁-C₆-alkyl, C₁-C₆-haloalkyl,    C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkoxycarbonyl and    C₁-C₆-haloalkoxycarbonyl; and-   R¹⁸ in the group S(O)_(m)R¹⁸ is additionally selected from the group    consisting of C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, aryloxy,    heterocyclyloxy and heteroaryloxy;-   each R¹⁹ is independently selected from the group consisting of    halogen, nitro, cyano, —OH, —SH, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,    C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, C₁-C₃-alkylsulfinyl,    C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,    C₁-C₆-haloalkylsulfonyl, Si(R¹⁴)₃;-    C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, wherein the two    last-mentioned cycloaliphatic radicals may carry one or more    radicals selected from the group consisting of cyano, C₁-C₄-alkyl,    C₁-C₄-haloalkyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl,    C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and oxo;-    aryl, aryloxy, heterocyclyl, heterocyclyloxy, heteroaryl and    heteroaryloxy, wherein the 6 last mentioned radicals may be    unsubstituted, partially or fully halogenated and/or carry 1, 2 or    3, in particular 1, substituents selected from the group consisting    of C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,    C₁-C₆-alkoxycarbonyl and C₁-C₆-haloalkoxycarbonyl;-   each R²⁰ is independently defined as R¹⁸;-   R²¹, R^(21a) and R^(21b), independently of each other and    independently of each occurrence, are selected from the group    consisting of hydrogen, cyano, alkyl, cycloalkyl, alkenyl, alkynyl,    wherein the four last-mentioned aliphatic and cycloaliphatic    radicals may be partially or fully halogenated, and/or the four    last-mentioned aliphatic and cycloaliphatic radicals carry one or    more substituents selected from the group consisting of cyano, OH,    C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy,    C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,    C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,    C₁-C₆-haloalkylsulfonyl, formyl, C₁-C₄-alkylcarbonyl,    C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,    C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino and    di-(C₁-C₄-alkyl)amino;-    aryl, aryl-C₁-C₄-alkyl, heterocyclyl, and heteroaryl, where the    rings in the 4 last mentioned radicals may be substituted with 1, 2,    3, 4, or 5 substituents R¹⁵;-    or R^(21a) and R^(21b), together with the nitrogen atom to which    they are bound, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated,    partially unsaturated or maximally unsaturated heterocyclic,    inclusive heteroaromatic, ring, where the ring may further contain    1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected    from the group consisting of O, S, N, SO, SO₂, C═O and C═S as ring    members, wherein the heterocyclic ring may be substituted with 1, 2,    3, 4 or 5 substituents independently selected from R¹⁵;-   each R²² is independently defined as R¹⁶;-   each R²³ is independently selected from the group consisting of    hydrogen, halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy,    C₁-C₆-haloalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,    C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,    C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,    C₃-C₈-halocycloalkyl, and phenyl, optionally substituted with 1, 2,    3, 4, or 5 radicals selected from the group consisting of halogen,    cyano, nitro, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy and    C₁-C₆-haloalkoxy; and-   m is 0, 1 or 2.

In the above radicals, all functional groups, especially halogen atomsand sulfonyloxy groups, have to be less reactive towards the organoboroncompound than the halogen atom or sulfonate group on the desiredreaction site of the R²—(Z)_(n) compound.

Specifically, R¹ and R² are aryl or heteroaryl groups, Y is OH or formsa MIDA ester, Z is a halide, especially Cl or Br, and n is 1 or 2.

The organoboron compounds are either commercially available or can beprepared by known methods; see e.g. the below-described Miyauraborylation.

The organoboron compound and the halogenide or sulfonate can be used ina molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to1:5. In case of di- or polyfunctional halides or sulfonates, the molarratio relates of course to the number of halide or sulfonate groups inthe molecule. The organoboron compounds are however generally used in atleast equimolar amount (in case of di- or polyfunctional halides orsulfonates, the at least equimolar amount refers of course to the amountof halide or sulfonate groups; i.e. for 1 mol of Z—R²—Z at least 2 molof R¹—BY₂ are used), e.g. from equimolar amount to a fivefold or inparticular threefold or especially twofold excess or 1.5-fold excess(again, in case of di- or polyfunctional halides or sulfonates, theexcess amount refers of course to the amount of halide or sulfonategroups; i.e. for 1 mol of Z—R²—Z 10 mol of R¹—BY₂ are used for afivefold excess). If however the halide or sulfonate is more easilyavailable and/or less expensive than the organoboron compound, this caninstead be used in excess, e.g. in a fivefold or threefold or twofold or1.5-fold excess. Especially in case that the organoboron compound is aMIDA ester, the organoboron compound and the halide or sulfonate can beused in approximately equimolar amounts.

The Pd catalyst can generally either be used as a salt (e.g. Pd(II)acetate or Na₂PdCl₄) or, more often, as a Pd(II) complex which is eitherpreformed or prepared in situ from a Pd(II) salt (e.g. Pd(II)acetate orPdCl₂) and the respective ligand. The same applies to Ni catalysts.Suitable ligands for the complex often contain phosphorus. Examples forphosphorus ligands aredi-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)-phosphine (cBRIDP;Mo-Phos), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (t-BuXPhos, tBuXPhos, tert-Butyl XPhos), 1,1′-bis(diphenylphosphino)ferrocene(dppf), 1,1′-bis(di-tert-butylphosphino)ferrocene (dtbpf),1,2-bis(diphenylphosphino)ethane (dppe),1,3-bis(diphenylphosphino)propane (dppp),1,4-bis(diphenylphosphino)butane (dppb),(2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane(diop), bis(di-tert-butyl(4-dimethylaminophenyl)-phosphine) (Amphos),(2S,3S)-(−)-bis(diphenylphosphino)butane (Chiraphos),di-(tert-butyl)phenylphosphine,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP),[1,1′-biphenyl]-2-diisopropyl phosphine,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos),4,5-bis-(di-1-(3-methylindolyl)-phosphoramidit)-2,7,9,9-tetramethylxanthene(MeSkatOX), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-phos),2-(2-dicyclohexylphosphanylphenyl)-N1,N1,N3,N3-tetramethyl-benzene-1,3-diamine(C-phos),6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphine,[(4R)-(4,4′-bis-1,3-benzodioxole)-5,5′-diyl]bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphine]((R)-DTBM-SEGPHOS®), (R)- or (S)-3,5-Xyl-MeO-BIPHEP, (R,S)- or(S,R)-PPF-P(t-Bu)₂, the Josiphos ligands, triphenylphosphine,triphenylphosphite,tri-(2-(1,1-dimethylethyl)-4-methoxy-phenyl)-phosphite,tricyclohexylphosphine, tri(tert-butyl)phosphine,butyldi-1-adamantylphosphine (cataCXium),1,6-bis(diphenylphosphino)hexane (DPPH),2,6-bis(2,5-dimethylphenyl)-1-octyl-4-phenylphosphacyclohexan (PCH),tris(3-sulfophenyl)phosphine trisodium salt (TPPTS) and the like.

Non-phosphorus ligands are for example bis(dibenzylideneacetone) (dba),acetonitrile, bisoxazoline and the like. Further, examples for Pdcatalysts with ligands without phosphorus are the above-mentioned PEPPSIcatalysts (inclusive the new generation).

Examples for catalysts are Pd(Cl)₂(dtbpf), PdCl₂(dppf), Pd(PPh₃)₄,Pd(Cl)₂(t-Bu₂PPh)₂, Pd(Cl)₂(Amphos)₂, Pd(OAc)₂-TPPTS, (OAc=acetate,Ph=phenyl), Pd(dba)₂, the above PEPPSI catalysts (inclusive the newgeneration), Ni(Cl)₂(dtbpf), Ni(Cl)₂(dppf), Ni(Cl)₂(dppp), and the like.

Suitable bases can be inorganic or organic. Examples for suitableinorganic bases are alkali metal carbonates, e.g. Li₂CO₃, Na₂CO₃, K₂CO₃or Cs₂CO₃, alkali metal hydroxides, e.g. LiOH, NaOH or KOH, orphosphates, e.g. Li₃PO₄, Na₃PO₄, K₃PO₄ or Cs₃PO₄. Examples for suitableorganic bases are open-chained amines, e.g. trimethylamine,triethylamine, tripropylamine, ethyldiisopropylamine and the like, basicN-heterocycles, such as morpoline, pyridine, lutidine, DABCO, DBU orDBN, alkoxylates, e.g. sodium or potassium methanolate, ethanolate,propanolate, isopropanolate, butanolate or tert-butanolate, especiallysterically hindered alkoxylates, such as sodium or potassiumtert-butanolate, silanolates, like sodium or potassiumtrimethylsilanolate ((CH₃)₃SiO⁻) or triisopropylsilanolate((CH(CH₃)₂)₃SiO⁻), phosphazene bases (superbases), such as BEMP andt-Bu-P4

or phenolates, especially sterically hindered phenolates, like thesodium or potassium salts of the following hydroxyaromatic compounds:

wherein R is H or optionally substituted C₁-C₂-alkyl, e.g. methyl,CH₂—N(CH₃)₂ or CH₂CH₂—C(O)—O—C₁₈H₂₁.

The alkoxylates, phenolates and silanolates are either commerciallyavailable or can be prepared shortly before starting the reaction or insitu by reaction of the respective alcohol/hydroxyaromaticcompound/silanol with NaOH or KOH.

Specifically, the present method relates to a Suzuki reaction in whichan aromatic or heteroaromatic halide R²—(Z)_(n), where R² is a mono-,bi- or polycyclic, especially a mono-, bi- or tricyclic aryl orheteroaryl group, Z is a halogen atom, especially Cl, Br or I, and n is1 or 2, is reacted with an aromatic or heteroaromatic boron compoundR¹—BY₂, wherein R¹ is a mono-, bi- or polycyclic, especially a mono-,bi- or tricyclic aryl or heteroaryl group and Y is OH or the two Y formtogether a group —O—C(═O)—CH₂—N(CH₃)—CH₂—C(═O)—O—, in the presence of aPd catalyst, specifically of PdCl₂(dtbpf), and in the presence of abase, specifically of an organic base, very specifically an amine.

In a particular embodiment aryl groups R¹ and R² are mono-, bi- ortricyclic and are specifically selected from the group consisting ofphenyl and naphthyl; and heteroaryl groups R¹ and R² are in particularmono-, bi- or tricyclic and are specifically selected from the groupconsisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4heteroatoms selected from the group consisting of N, O and S as ringmembers. Mono- or bicyclic aryl or heteroaryl groups R¹ and R² are forexample phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl,[1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls,the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl,pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl,benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. Moreparticularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl,3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl,1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl,1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl,1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl,1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl,1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl,4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl,3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl,1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl,1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl,benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl,quinazalinyl and other heteroaromatic bicyclic rings shown below in the“general definitions”.

The aryl and heteroaryl groups R¹ and R² can carry one or moresubstituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1or 2 substituents. Suitable substituents are listed above in contextwith aryl and heteroaryl groups R¹ and R² in the Suzuki reaction. In aparticular embodiment, the substituents on the aryl and heteroarylgroups R¹ and R² are selected from the group consisting of fluorine,cyano, nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members and a 9- or 10-memberedheteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members, wherephenyl and the heteroaromatic rings may carry one or more substituentsselected from the group consisting of fluorine, cyano, nitro, OH, SH,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino. Specifically, the substituents on the aryl andheteroaryl groups R¹ and R² are selected from the group consisting offluorine, cyano, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 25° C. to 55° C. andvery specifically from 40° C. to 50° C.

If n is 1, R²—(Z)_(n) and R¹—BY₂ are in particular used in a molar ratioof from 0.8:1 to 1:4, more particularly from 1:1 to 1:3 and specificallyfrom 1:1 to 1:2. If n is 2, R²—(Z)_(n) and R¹—BY₂ are in particular usedin a molar ratio of from 1:1.5 to 1:8, more particularly from 1:2 to 1:6and specifically from 1:2 to 1:5.

The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g.in an amount of from 0.001 to 0.1 mol per mol of that reactant which notused in excess (here mostly the compound R²—(Z)_(n)), in particular0.005 to 0.07 mol per mol of the reactant not used in excess,specifically 0.01 to 0.05 mol per mol of the reactant not used inexcess. If the reactants are used in equimolar ratio, the above amountsof catalyst apply of course to either of the reactants.

The base is generally used in excess, i.e. in overstoichiometric amountswith respect to that reactant not used in excess, e.g. in an amount offrom 1.5 to 5 mol per mol of the reactant not used in excess, inparticular 2 to 4 mol per mol of the reactant not used in excess. If thereactants are used in equimolar ratio, the above amounts of base applyof course to either of the reactants.

The reaction can be carried out by standard proceedings for Suzukireactions, e.g. by mixing all reagents, inclusive catalyst or catalystprecursor and ligand(s) and base, water and the cellulose derivative andreacting them at the desired temperature. Alternatively the reagents canbe added gradually, especially in the case of a continuous orsemicontinuous process.

If the catalyst ligand or any reactant is prone to oxidation by air(such as is the case, for example, for triphenylphosphine,tri(tert-butyl)phosphine, X-Phos,6,6-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphineand several others), the reaction is preferably carried out in an inertatmosphere in order to avoid the presence of oxygen, e.g. under an argonor nitrogen atmosphere. Preferably, moreover, the solvent is used indegassed form. On a laboratory scale this is e.g. obtained by freezing,applying a vacuum and unfreezing under an inert atmosphere or bybubbling a vigorous stream of argon or nitrogen through the solvent orby ultrasonification under an inert atmosphere. On an industrial scaleother methods known in the art can be applied.

Workup proceedings will be described below, as they are similar for mostreactions.

Sonogashira Reaction

In another particular embodiment the transition metal catalyzed C—Ccoupling reaction is a Sonogashira reaction. In Sonogashira reactions anaryl, heteroaryl or vinyl halogenide or sulfonate (the sulfonate beingin particular a fluorinated alkylsulfonate or tosylate, specificallytriflate or nonaflate) is reacted with a terminal alkyne. Preferably, ahalogenide or sulfonate R²—(Z)_(n), where R² is an alkenyl (especially aterminal alkenyl; i.e. Z is bound to a carbon atom of a C—C doublebond), aryl or heteroaryl group, Z is a halogenide or sulfonate (thesulfonate being in particular a fluorinated alkylsulfonate or tosylate,specifically triflate or nonaflate) group and n is 1, 2, 3 or 4, isreacted with a terminal alkyne H—C≡C—R¹, where R¹ is hydrogen or analkyl, alkenyl, alkapolyenyl, alkynyl (provided that the C—C triple bondis not terminal), alkapolyynyl (provided there is no terminal C—C triplebond (—C≡C—H) in this radical), mixed alkenyl/alkynyl (provided there isno terminal C—C triple bond (—C≡C—H) in this radical), cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, heterocyclyl, aryl, heteroaryl or silyl group Si(R¹⁴)₃,in the presence of a transition metal catalyst, mostly a Pd catalyst,optionally of a copper(I) salt, and in general also of a base. Each R¹⁴′has independently one of the meanings given above in context with theSuzuki reaction for R¹⁴. Classically, the Sonogashira coupling involvesthe use of a copper salt. In the present invention, however, the term“Sonogashira reaction” or “Sonogashira coupling” is also used for thecoupling of an aryl, heteroaryl or vinyl halogenide or sulfonate with aterminal alkyne in the presence of a transition metal catalyst, mostly aPd catalyst, and in general also of a base, but without copper(salts/complexes).

The reaction of the terminal alkyne with R²—(Z)_(n) yields a compound(R¹)_(n)—R². The alkenyl, aryl or heteroaryl halide or sulfonate cancontain more than one halide or sulfonate group (when n is 2, 3 or 4),so that multiply coupled compounds can form, especially if the alkynecompound is used in excess. For instance, a difunctional compoundR²—(Z)₂ can yield a twofold coupled compound R¹—R²—R¹.

Due to the tolerance of the Sonogashira reaction to a wide variety offunctional groups, the alkyl, alkenyl, alkapolyenyl, alkynyl, mixedalkenyl/alkynyl, alkapolyynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl orheteroaryl groups R¹ and R² can carry one or more substituents. Suitablesubstituents for the alkyl, alkenyl, alkapolyenyl, alkynyl, mixedalkenyl/alkynyl, alkapolyynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroarylgroups correspond to those listed above in context with substituents onthe alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling. Suitable substituents for heterocyclylgroups R¹ and R² correspond to those listed above in context withsubstituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling.

In these substituents, however, all functional groups, especiallyhalogen atoms and sulfonyloxy groups, have to be less reactive towardsthe alkyne compound than the halogen atom or sulfonate group on thedesired reaction site of the R²—(Z)_(n) compound.

Suitable Pd catalysts (inclusive ligands) are those mentioned above incontext with the Suzuki coupling.

Suitable Cu(I) salts are CuI and CuBr.

Suitable bases are those mentioned above in context with the Suzukicoupling.

Specifically, the present method relates to a Sonogashira reaction inwhich an aromatic or heteroaromatic halogenide R²—(Z)_(n), where R² is amono-, bi- or polycyclic aryl or heteroaryl group, Z is a halogen atom,especially Cl, Br or I, more specifically Br or I, and n is 1, isreacted with a terminal alkyne H—C≡C—R¹, where R¹ is a mono-, bi- orpolycyclic aryl or heteroaryl group, in the presence of a Pd catalyst,specifically of PdCl₂(CH₃CN)₂ or PdCl₂(X-Phos)₂, and in the presence ofa base, specifically of an alkali metal carbonate, very specificallyCs₂CO₃, or an organic base, specifically an amine.

In a particular embodiment aryl groups R¹ and R² are mono-, bi- ortricyclic and are specifically selected from the group consisting ofphenyl and naphthyl; and heteroaryl groups R¹ and R² are in particularmono-, bi- or tricyclic and are specifically selected from the groupconsisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4heteroatoms selected from the group consisting of N, O and S as ringmembers. Mono- or bicyclic aryl or heteroaryl groups R¹ and R² are forexample phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl,[1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls,the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl,pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl,benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. Moreparticularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl,3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl,1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl,1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl,1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl,1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl,1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl,4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl,3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl,1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl,1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl,benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl,quinazalinyl and other heteroaromatic bicyclic rings shown below in the“general definitions”.

The aryl and heteroaryl groups R¹ and R² can carry one or moresubstituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1or 2 substituents. Suitable substituents are listed above in contextwith aryl and heteroaryl groups R¹ and R² in the Suzuki reaction. In aparticular embodiment, the substituents on the aryl and heteroarylgroups R¹ and R² are selected from the group consisting of fluorine,cyano, nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, Oand S as ring members and a 9- or 10-membered heteroaromatic bicyclicring containing 1, 2, 3 or 4 heteroatoms selected from the groupconsisting of N, O and S as ring members, where phenyl and theheteroaromatic rings may carry one or more substituents selected fromthe group consisting of fluorine, cyano, nitro, OH, SH, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl, C₂-C₆-alkynyl,C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, formyl, C₁-C₄-alkylcarbonyl,C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl,amino, C₁-C₄-alkylamino and di-(C₁-C₄-alkyl)amino. Specifically, thesubstituents on the aryl and heteroaryl groups R¹ and R² are selectedfrom the group consisting of fluorine, cyano, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl,C₃-C₈-cycloalkyl-C₁-C₆-alkyl, C₃-C₈-halocycloalkyl-C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, formyl, C₁-C₄-alkylcarbonyl,C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl,amino, C₁-C₄-alkylamino and di-(C₁-C₄-alkyl)amino.

Very specifically, R¹ and R² are selected from the group consisting ofphenyl and naphthyl, where phenyl and naphthyl may carry 1, 2 or 3,specifically 1 or 2 substituents as defined above.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 20° C. to 50° C. andvery specifically from 20° C. to 30° C.

The halogenide or sulfonate and the terminal alkyne can be used in amolar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to1:5. In case of di- or polyfunctional halides or sulfonates, the molarratio relates of course to the number of halide or sulfonate groups inthe molecule. If n is 1, R²—(Z)_(n) and H—C≡C—R¹ are preferably used ina molar ratio of from 2:1 to 1:2, more preferably from 1.5:1 to 1:1.5and specifically in approximately equimolar amounts. If n is 2,R²—(Z)_(n) and H—C≡C—R¹ are preferably used in a molar ratio of from 1:1to 1:4, more preferably from 1:1.5 to 1:3 and specifically in a molarratio of ca. 1:2. “ca.” and “approximately” include weighing errors of+/−10%.

The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g.in an amount of from 0.001 to 0.1 mol per mol of that reactant which isnot used in excess, in particular 0.005 to 0.07 mol per mol of thereactant not used in excess, specifically 0.005 to 0.05 mol per mol ofthe reactant not used in excess. If the reactants are used in equimolarratio, the above amounts of catalyst apply of course to either of thereactants.

The base is generally used in excess, i.e. in overstoichiometric amountswith respect to that reactant not used in excess, e.g. in an amount offrom 1.5 to 5 mol per mol of the reactant not used in excess, inparticular 1.5 to 4 mol per mol of the reactant not used in excess,specifically 1.5 to 3 mol per mol of the reactant not used in excess. Ifthe reactants are used in equimolar ratio, the above amounts of baseapply of course to either of the reactants.

The reaction can be carried out by standard proceedings for Sonogashirareactions, e.g. by mixing all reagents, inclusive catalyst or catalystprecursor and ligand(s) and base, water and the cellulose derivative andreacting them at the desired temperature. Alternatively the reagents canbe added gradually, especially in the case of a continuous orsemicontinuous process.

If the catalyst ligand or any reactant is prone to oxidation by air(such as is the case, for example, for triphenylphosphine,tri(tert-butyl)phosphine, X-Phos,6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphineand several others), the reaction is preferably carried out in an inertatmosphere in order to avoid the presence of oxygen, e.g. under an argonor nitrogen atmosphere. Preferably, moreover, the solvent is used indegassed form. On a laboratory scale this is e.g. obtained by freezing,applying a vacuum and unfreezing under an inert atmosphere or bybubbling a vigorous stream of argon or nitrogen through the solvent orby ultrasonification under an inert atmosphere. On an industrial scaleother methods known in the art can be applied.

Workup proceedings will be described below, as they are similar for mostreactions.

Heck Reaction

In another particular embodiment the transition metal catalyzed C—Ccoupling reaction is a Heck reaction. In Heck reactions an aryl,heteroaryl, benzyl, vinyl or alkyl halogenide or sulfonate (the alkylgroup must not contain any β-hydrogen atoms) is reacted with anolefinically unsaturated compound in the presence of a transition metalcatalyst, mostly a Pd catalyst, and generally also in the presence of abase. The sulfonate is in particular a fluorinated alkylsulfonate ortosylate, specifically triflate, nonaflate or tosylate.

Preferably, a halogenide or sulfonate R²—(Z)_(n), where R² is an aryl,heteroaryl, benzyl, vinyl or alkyl group (the alkyl group must howevernot contain any β-hydrogen atoms), Z is a halogen atom or a sulfonategroup (the sulfonate being in particular a fluorinated alkylsulfonate ortosylate, specifically triflate, nonaflate or tosylate), preferably aCl, Br, I, triflate, nonaflate or tosylate group, and n is 1, 2, 3 or 4,is reacted with an olefin R¹(H)C═C(R³)(R⁴) where R¹, R³, and R⁴,independently of each other, are hydrogen, alkyl, alkenyl, alkapolyenyl,alkynyl, alkapolynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl,heterocyclyl, aryl, heteroaryl, or are one of the substituents listed incontext with the Suzuki reaction as suitable radicals on alkyl, alkenyl,alkapoyenyl, alkynyl, alkapolyynyl or mixed alkenyl/alkynyl groups(however except for oxo (═O), ═S, and ═NR^(12a)), in the presence of atransition metal catalyst, mostly a Pd catalyst, and in general also ofa base. More precisely, R¹, R³ and R⁴, independently of each other, arehydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl,heteroaryl, halogen, cyano, nitro, azido, —SCN, —SF₅, OR¹¹, S(O)_(m)R¹¹,NR^(12a)R^(12b), C(═O)R¹³, C(═S)R¹³, C(═NR^(12a))R¹³ or —Si(R¹⁴)₃; whereR¹¹, R^(12a), R^(12b), R¹³, R¹⁴ and R¹⁵ are independently as definedabove in context with the Suzuki reaction. The reaction yields acompound (R¹)_(n)—R². The halogenide or sulfonate can contain more thanone halogenide or sulfonate group (when n is 2, 3 or 4), so thatmultiply coupled compounds can form, especially if the olefinic compoundis used in excess. For instance, a difunctional compound R²—(Z)₂ canyield a twofold coupled compound R¹—R²—R¹.

Due to the tolerance of the Heck reaction to a wide variety offunctional groups, the alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl,heterocyclyl, aryl, heteroaryl, benzyl, vinyl groups R¹, R², R³ and R⁴can carry one or more substituents. Suitable substituents for the on thealkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groupscorrespond to those listed above in context with substituents on thealkyl, alkenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, aryl or heteroaryl groups R¹ and R² in the Suzukicoupling. Suitable substituents for heterocyclyl groups correspond tothose listed above in context with substituents on the cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, aryl or heteroaryl groups R¹ and R² in the Suzukicoupling. Specifically, the cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl, heterocyclyl andheteroaryl groups R¹, R³ and R⁴ may be substituted by one or moreradicals R¹⁵.

In these substituents, however, all functional groups, especiallyhalogen atoms and sulfonyloxy groups, have to be less reactive towardsthe olefinic compound than the halogen atom or sulfonate group on thedesired reaction site of the R²—(Z)_(n) compound. Analogously, if in theolefinic compound R¹(H)C═C(R³)(R⁴) the radicals R¹, R³, and/or R⁴contain C—C double (or also triple) bonds, these have to be lessreactive towards Z than the C—C double bond at the desired reaction siteof R¹(H)C═C(R³)(R⁴).

Suitable Pd catalysts (inclusive ligands) are those mentioned above incontext with the Suzuki coupling.

Suitable bases are those mentioned above in context with the Suzukicoupling.

Specifically, the present method relates to a Heck reaction in which anaromatic or heteroaromatic halogenide R²—(Z)_(n), where R² is a mono-,bi- or polycyclic aryl or heteroaryl group, Z is a halogen atom,especially Cl, Br or I, more specifically Br or I, and n is 1, isreacted with an olefinic compound R¹(H)C═C(R³)(R⁴) where R¹ and R³ are Hand R⁴ is hydrogen, alkyl, or is one of the substituents listed incontext with the Suzuki reaction as suitable radicals on alkyl, alkenyland alkynyl groups (and is more precisely hydrogen, alkyl, halogen,cyano, nitro, azido, —SCN, —SF₅, OR¹¹, S(O)_(m)R¹¹, NR^(12a)R^(12b),C(═O)R¹³, C(═S)R¹³, C(═NR^(12a))R¹³ or —Si(R¹⁴)₃), in the presence of aPd catalyst, specifically of Pd(t-Bu₃P)₂, and in the presence of a base,specifically an amine.

In a particular embodiment the aryl group R² is mono-, bi- or tricyclicand is specifically selected from the group consisting of phenyl andnaphthyl; and the heteroaryl group R² is in particular mono-, bi- ortricyclic and is specifically selected from the group consisting of 5-or 6-membered heteroaromatic monocyclic rings and 9- or 10-memberedheteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members. Mono-or bicyclic aryl or heteroaryl groups R² are for example phenyl,naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl,isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl,[1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls,pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl,isoquinolinyl, quinazalinyl and the like. More particularly, they arefor example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl,1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl,1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl,1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl,1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl,4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl,1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl,1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl,indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromaticbicyclic rings shown below in the “general definitions”.

The aryl and heteroaryl groups R² can carry one or more substituents,e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2substituents. Suitable substituents are listed above in context witharyl and heteroaryl groups R¹ and R² in the Suzuki reaction. In aparticular embodiment, the substituents on the aryl and heteroarylgroups R² are selected from the group consisting of fluorine, cyano,nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, Oand S as ring members and a 9- or 10-membered heteroaromatic bicyclicring containing 1, 2, 3 or 4 heteroatoms selected from the groupconsisting of N, O and S as ring members, where phenyl and theheteroaromatic rings may carry one or more substituents selected fromthe group consisting of fluorine, cyano, nitro, OH, SH, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl, C₂-C₆-alkynyl,C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, formyl, C₁-C₄-alkylcarbonyl,C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl,amino, C₁-C₄-alkylamino and di-(C₁-C₄-alkyl)amino. Specifically, thesubstituents on the aryl and heteroaryl groups R² are selected from thegroup consisting of fluorine, cyano, C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino.

Particular groups R⁴ are halogen (provided that this not more reactivethan the halogen atom or sulfonate group on the desired reaction site ofthe R²—(Z)_(n) compound) cyano, nitro, azido, —SCN, —SF₅, OR¹¹,S(O)_(m)R¹¹, NR^(12a)R^(12b), C(═O)R¹³, C(═S)R¹³, C(═NR^(12a))R¹³,—Si(R¹⁴)₃, alkyl, optionally substituted by one or more radicals R¹⁷;cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, where the 5 last-mentioned substituents may carry oneor more substituents selected from R¹⁵; aryl which may be substituted byone or more radicals R¹⁵, heterocyclyl may be substituted by one or moreradicals R¹⁵; and heteroaryl which may be substituted by one or moreradicals R¹⁵; where R¹¹, R^(12a), R^(12b), R¹³, R¹⁴, R¹⁵ and R¹⁷ are asdefined above in context with the Suzuki reaction. Specifically, R⁴ isC(═O)R¹³, where R¹³ is alkyl or alkoxy, specifically C₁-C₆-alkyl orC₁-C₆-alkoxy and very specifically C₁-C₆-alkoxy.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 25° C. to 55° C. andvery specifically from 40° C. to 50° C.

The halogenide or sulfonate and the olefinically unsaturated compoundcan be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7or from 5:1 to 1:5. In case of di- or polyfunctional halogenides orsulfonates, the molar ratio relates of course to the number ofhalogenide or sulfonate groups in the molecule. If n is 1, R²—(Z)_(n)and R¹(H)C═C(R³)(R⁴) are preferably used in a molar ratio of from 0.8:1to 1:4, more preferably from 1:1 to 1:3 and specifically from 1:1 to1:2. If n is 2, R²—(Z)_(n) and R¹(H)C═C(R³)R⁴) are preferably used in amolar ratio of from 1:1.5 to 1:8, more preferably from 1:2 to 1:6 andspecifically from 1:2 to 1:5.

The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g.in an amount of from 0.001 to 0.1 mol per mol of that reactant which isnot used in excess, in particular 0.005 to 0.07 mol per mol of thereactant not used in excess, specifically 0.01 to 0.05 mol per mol ofthe reactant not used in excess. If the reactants are used in equimolarratio, the above amounts of catalyst apply of course to either of thereactants.

The base is generally used in excess, i.e. in overstoichiometric amountswith respect to that reactant not used in excess, e.g. in an amount offrom 1.5 to 5 mol per mol of the reactant not used in excess, inparticular 1.5 to 4 mol per mol of the reactant not used in excess,specifically 2 to 4 mol per mol of the reactant not used in excess. Ifthe reactants are used in equimolar ratio, the above amounts of baseapply of course to either of the reactants.

The reaction can be carried out by standard proceedings for Heckreactions, e.g. by mixing all reagents, inclusive catalyst or catalystprecursor and ligand(s) and base, water and the cellulose derivative andreacting them at the desired temperature. Alternatively the reagents canbe added gradually, especially in the case of a continuous orsemicontinuous process.

If the catalyst ligand or any reactant is prone to oxidation by air(such as is the case, for example, for triphenylphosphine,tri(tert-butyl)phosphine, X-Phos,6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphineand several others), the reaction is preferably carried out in an inertatmosphere in order to avoid the presence of oxygen, e.g. under an argonor nitrogen atmosphere. Preferably, moreover, the solvent is used indegassed form. On a laboratory scale this is e.g. obtained by freezing,applying a vacuum and unfreezing under an inert atmosphere or bybubbling a vigorous stream of argon or nitrogen through the solvent orby ultrasonification under an inert atmosphere. On an industrial scaleother methods known in the art can be applied.

Workup proceedings will be described below, as they are similar for mostreactions.

C—C Coupling Reactions Involving C—H Activation

In another particular embodiment the transition metal catalyzed C—Ccoupling reaction is C—C coupling reaction involving C—H activation.Such reactions are coupling reactions in which one of the reactantsreacts via a C—H bond and not via a specific activating group. The Heckreaction is such a reaction involving C—H activation. In the presentcase however, in the C—C coupling reactions involving C—H activation twoaromatic or heteroaromatic compounds are coupled.

In a particular embodiment of the present invention, a halogenide orsulfonate R²—Z, where R² is an aryl or heteroaryl group, Z is a halogenatom (Cl, Br and I being preferred) or a sulfonate group (the sulfonatebeing in particular a fluorinated alkylsulfonate or tosylate,specifically triflate, nonaflate or tosylate), and is preferably I, isreacted with a compound R¹—H, where R¹ is an aryl or heteroaryl group,in the presence of a transition metal catalyst, mostly a Pd catalyst,often under acidic conditions. If Z is Cl, Br or I, it may beadvantageous to carry out the reaction in the presence of awater-soluble silver(I) salt, which precipitates the eliminatedchloride, bromide or iodide ion as AgCl, AgBr or AgI and draws thereaction to the product side. The reaction yields a compound R¹—R².Preferably, R¹ carries in ortho position to the shown hydrogen atom aheteroatom-directing group. This group helps the transition metal tocoordinate to the substrate. Such heteroatom-directing groups are forexample amino groups, carbonylamino groups, urea groups, carbonylgroups, carboxyl groups, carboxylic ester groups, carboxamide groups andthe like. Particularly useful are urea groups, especially urea groupswith electron-donating groups, e.g. alkyl-substituted urea groups, suchas (C₁-C₄-alkyl)₂N—C(O)—NH—.

In a particular embodiment aryl groups R¹ and R² are mono-, bi- ortricyclic and are specifically selected from the group consisting ofphenyl and naphthyl; and heteroaryl groups R¹ and R² are in particularmono-, bi- or tricyclic and are specifically selected from the groupconsisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4heteroatoms selected from the group consisting of N, O and S as ringmembers. Mono- or bicyclic aryl or heteroaryl groups R¹ and R² are forexample phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl,[1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls,the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl,pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl,benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. Moreparticularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl,3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl,1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl,1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl,1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl,1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl,1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl,4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl,3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl,1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl,1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl,benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl,quinazalinyl and other heteroaromatic bicyclic rings shown below in the“general definitions”.

The aryl and heteroaryl groups R¹ and R² can carry one or moresubstituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1or 2 substituents. Suitable substituents are listed above in contextwith aryl and heteroaryl groups R¹ and R² in the Suzuki reaction.

In these substituents, however, all functional groups, especiallyhalogen atoms and sulfonyloxy groups, have to be less reactive towardsthe alkyne compound than the halogen atom or sulfonate group on thedesired reaction site of the R²—Z compound.

In a particular embodiment, the substituents on the aryl and heteroarylgroups R¹ and R² are selected from the group consisting of fluorine,cyano, nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members and a 9- or 10-memberedheteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members, wherephenyl and the heteroaromatic rings may carry one or more substituentsselected from the group consisting of fluorine, cyano, nitro, OH, SH,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino. Specifically, the substituents on the aryl andheteroaryl groups R¹ and R² are selected from the group consisting offluorine, cyano, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino.

Very specifically, R¹ and R² are selected from the group consisting ofphenyl and naphthyl, where phenyl and naphthyl may carry 1, 2 or 3,specifically 1 or 2 substituents as defined above. As said, preferably,R¹ carries in ortho position to the shown hydrogen atom aheteroatom-directing group.

Suitable Pd catalysts (inclusive ligands) are those mentioned above incontext with the Suzuki coupling. Particularly, however, the Pd catalystis used in form of a salt, e.g. as PdCl₂ or, in particular Pd(OAc)₂(OAc=acetate).

The Ag salt, if present, is in particular used as a water-soluble salt,e.g. AgNO₃ or, in particular, AgOAc.

The reaction is preferably carried out in acidic medium, so that theelectrophilic attack on the (het)aryl ring is facilitated. Suitableacids are for example HBF₄, trifluoroacetic acid, toluenesulfonic acidand acetic acid.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 20° C. to 50° C. andvery specifically from 20° C. to 30° C.

The halogenide or sulfonate and the C—H compound can be used in a molarratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5;preferably from 4:1 to 1:4, in particular from 3:1 to 1:3 andspecifically from 2:1 to 1:2.

The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g.in an amount of from 0.001 to 0.5 mol per mol of that reactant which isnot used in excess, in particular 0.01 to 0.5 mol per mol of thereactant not used in excess, specifically 0.05 to 0.3 mol per mol of thereactant not used in excess. If the reactants are used in equimolarratio, the above amounts of catalyst apply of course to either of thereactants.

The silver(I) salt is preferably used in such an amount that it canprecipitate all the theoretically eliminated halide ions. Accordingly,it is preferably used in at least equimolar amounts with respect to thehalide R²—Z, e.g. in a weight ratio of Ag salt to halide of from 1:1 to2:1, in particular 1:2 to 1.5:1 and specifically in approximatelyequimolar amounts “Approximately” includes weighing errors of +/−10%.

The acid is generally used in excess, i.e. in overstoichiometric amountswith respect to that reactant not used in excess, e.g. in an amount offrom 1.5 to 5 mol per mol of the reactant not used in excess, inparticular 1.5 to 4 mol per mol of the reactant not used in excess,specifically 2 to 4 mol per mol of the reactant not used in excess. Ifthe reactants are used in equimolar ratio, the above amounts of baseapply of course to either of the reactants.

The reaction can be carried out by standard proceedings for C—C couplingreactions reactions involving C—H activation, e.g. by mixing allreagents, inclusive catalyst or catalyst precursor and ligand(s), silversalt, if used, acid, if used, water and the cellulose derivative andreacting them at the desired temperature. Alternatively the reagents canbe added gradually, especially in the case of a continuous orsemicontinuous process.

If the catalyst ligand or any reactant is prone to oxidation by air(such as is the case, for example, for triphenylphosphine,tri(tert-butyl)phosphine, X-Phos,6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphineand several others), the reaction is preferably carried out in an inertatmosphere in order to avoid the presence of oxygen, e.g. under an argonor nitrogen atmosphere. Preferably, moreover, the solvent is used indegassed form. On a laboratory scale this is e.g. obtained by freezing,applying a vacuum and unfreezing under an inert atmosphere or bybubbling a vigorous stream of argon or nitrogen through the solvent orby ultrasonification under an inert atmosphere. On an industrial scaleother methods known in the art can be applied.

Workup proceedings will be described below, as they are similar for mostreactions.

Negishi Reaction

In another particular embodiment the transition metal catalyzed C—Ccoupling reaction is a Negishi reaction. In classical Negishi reactionsan organozinc compound is reacted with a halogenide, sulfonate (thesulfonate being in particular a fluorinated alkylsulfonate or tosylate,specifically triflate or nonaflate) or acetate in the presence of atransition metal catalyst, mostly a Pd or Ni catalyst, where the Pdcatalyst is often better suited. The reaction does not need the presenceof a further booster, such as the base in the Suzuki coupling. Insteadof organozinc compounds organoaluminum or organozirconium compounds canbe used. If these are not reactive enough they can be transmetallated tothe corresponding zinc compounds by addition of zinc salts (“doublemetal catalysis”).

In the present case, however, the organozinc compound (or theorganoaluminum or organozirconium compound) need not be preformed.Instead the precursor halide (of which the organozinc compound wouldnormally be formed), the other halogenide, sulfonate or acetate, atransition metal catalyst (mostly a Pd or Ni catalyst, better a Pdcatalyst) and Zn dust or powder are mixed in water in the presence ofthe cellulose derivative. It is assumed that the correspondingorganozinc compound is formed in situ and reacts then with thehalogenide, sulfonate or acetate. Preferably, a halide R¹—Z, where R¹ isan alkyl, alkenyl, alkynyl, aryl or heteroaryl group and Z is a halogenatom, especially Cl, Br or I, is reacted with a compound R²—(Z)_(n),where R² is an alkyl, alkenyl, alkynyl, aryl or heteroaryl group, Z is ahalogen atom, a sulfonate (the sulfonate being in particular afluorinated alkylsulfonate or tosylate, specifically triflate ornonaflate) or an acetate group and n is 1, 2, 3 or 4, in the presence ofa transition metal catalyst, mostly a Pd or Ni catalyst, where the Pdcatalyst is often better suited, Zn powder or dust to a compound(R¹)_(n)—R². The halogenide, sulfonate or acetate can contain more thanone halogenide, sulfonate or acetate group (when n is 2, 3 or 4), sothat multiply coupled compounds can form, especially if the organozinecompound is used in excess. For instance, a difunctional compoundR²—(Z)₂ can yield a twofold coupled compound R¹—R²—R¹. In a particularembodiment the reaction is moreover carried out in the presence of TMEDA(tetramethylethylendiamine), which presumably activates the Zn surface.

Due to the tolerance of the Negishi reaction to a wide variety offunctional groups, the alkyl, alkenyl, alkynyl, aryl or heteroarylgroups R¹ and R² can carry one or more substituents. Suitablesubstituents correspond to those listed above in context withsubstituents on the alkyl, alkenyl, alkynyl, aryl or heteroaryl groupsR¹ and R² in the Suzuki coupling.

In these substituents, however, all functional groups, especiallyhalogen atoms and sulfonyloxy groups, have to be less reactive towardsthe organozinc compound (formed in situ) than the halogen atom orsulfonate or acetate group on the desired reaction site of the R¹—Z andR²—(Z)_(n) compounds.

Suitable Pd and Ni catalysts (inclusive ligands) are those mentionedabove in context with the Suzuki coupling.

The precursor halide (of which the organozinc compound would normally beformed) or the organizing compound, if preformed, and the otherhalogenide, sulfonate or acetate can be used in a molar ratio of from10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5. In case of di- orpolyfunctional halogenides, sulfonates or acetates, the molar ratiorelates of course to the number of halogenide, sulfonate or acetategroups in the molecule.

The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g.in an amount of from 0.001 to 0.1 mol per mol of that reactant which isnot used in excess, in particular 0.005 to 0.07 mol per mol of thereactant not used in excess, specifically 0.01 to 0.05 mol per mol ofthe reactant not used in excess. If the reactants are used in equimolarratio, the above amounts of catalyst apply of course to either of thereactants.

If the catalyst ligand or any reactant is prone to oxidation by air(such as is the case, for example, for triphenylphosphine,tri(tert-butyl)phosphine, X-Phos,6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphineand several others), the reaction is preferably carried out in an inertatmosphere in order to avoid the presence of oxygen, e.g. under an argonor nitrogen atmosphere. Preferably, moreover, the solvent is used indegassed form. On a laboratory scale this is e.g. obtained by freezing,applying a vacuum and unfreezing under an inert atmosphere or bybubbling a vigorous stream of argon or nitrogen through the solvent orby ultrasonification under an inert atmosphere. On an industrial scaleother methods known in the art can be applied.

Workup proceedings will be described below, as they are similar for mostreactions.

Stille Coupling

In another particular embodiment the transition metal catalyzed C—Ccoupling reaction is a Stille reaction. In the Stille reaction, alsotermed Migita-Kosugi-Stille coupling, an organotin compound(organostannane) is reacted with an alkenyl, aryl, heteroaryl or acylhalide, sulfonate (the sulfonate being in particular a fluorinatedalkylsulfonate or tosylate, specifically triflate or nonaflate) orphosphate in the presence of a transition metal catalyst, mostly a Pdcatalyst, and sometimes also in the presence of a base.

Preferably, the organostannane compound is a compound of formulaR¹—Sn(R^(a))₃, where R¹ is a an alkenyl, aryl or heteroaryl group andR^(a) is an alkyl group, mostly butyl. The alkenyl, aryl, heteroaryl oracyl halide, sulfonate or phosphate is preferably a compound R²—(Z)_(n),where R² is an alkenyl, aryl, heteroaryl or acyl group, Z is a halogenatom, sulfonate (the sulfonate being in particular a fluorinatedalkylsulfonate or tosylate, specifically triflate or nonaflate) orphosphate group, preferably a Cl, Br, I, triflate, nonaflate orphosphate group, and n is 1, 2, 3 or 4. The reaction yields a compound(R¹)_(n)—R². The halogenide, sulfonate or phosphate can contain morethan one halogenide, sulfonate or phosphate group (when n is 2, 3 or 4),so that multiply coupled compounds can form, especially if theorganostannane compound is used in excess. For instance, a difunctionalcompound R²—(Z)₂ can yield a twofold coupled compound R¹—R²—R¹.

Due to the tolerance of the Stille reaction to a wide variety offunctional groups, the alkenyl, aryl and heteroaryl groups R¹ and R² cancarry one or more substituents. Suitable substituents correspond tothose listed above in context with substituents on the alkyl, alkenyl,aryl or heteroaryl groups R¹ and R² in the Suzuki coupling.

In these substituents, however, all functional groups, especiallyhalogen atoms and sulfonyloxy groups, have to be less reactive towardsthe organotin compound than the halogen atom or sulfonate or phosphategroup on the desired reaction site of the R²—(Z)_(n) compound.

Suitable Pd catalysts (inclusive ligands) are those mentioned above incontext with the Suzuki coupling.

Suitable bases are those mentioned above in context with the Suzukicoupling.

Specifically, the present method relates to a Stille reaction in whichan aromatic or heteroaromatic halogenide R²—(Z)_(n), where R² is amono-, bi- or polycyclic aryl or heteroaryl group, Z is a halogen atom,especially Cl, Br or I, more specifically Br or I, and n is 1, isreacted with an organostannane R¹—Sn(R^(a))₃, where R¹ is an aryl or inparticular an alkenyl group and R^(a) is butyl, a Pd catalyst,specifically of Pd(t-Bu₃P)₂, and in the presence of a base, specificallya basic heterocycle.

In a particular embodiment aryl groups R¹ and R² are mono-, bi- ortricyclic and are specifically selected from the group consisting ofphenyl and naphthyl; and heteroaryl groups R¹ and R² are in particularmono-, bi- or tricyclic and are specifically selected from the groupconsisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4heteroatoms selected from the group consisting of N, O and S as ringmembers. Mono- or bicyclic aryl or heteroaryl groups R¹ and R² are forexample phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl,[1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls,the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl,pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl,benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. Moreparticularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl,3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl,1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl,1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl,1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl,1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl,1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl,4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl,3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl,1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl,1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl,benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl,quinazalinyl and other heteroaromatic bicyclic rings shown below in the“general definitions”.

The aryl and heteroaryl groups R¹ and R² can carry one or moresubstituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1or 2 substituents. Suitable substituents are listed above in contextwith aryl and heteroaryl groups R¹ and R² in the Suzuki reaction. In aparticular embodiment, the substituents on the aryl and heteroarylgroups R¹ and R² are selected from the group consisting of fluorine,cyano, nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, Oand S as ring members and a 9- or 10-membered heteroaromatic bicyclicring containing 1, 2, 3 or 4 heteroatoms selected from the groupconsisting of N, O and S as ring members, where phenyl and theheteroaromatic rings may carry one or more substituents selected fromthe group consisting of fluorine, cyano, nitro, OH, SH, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl, C₂-C₆-alkynyl,C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, formyl, C₁-C₄-alkylcarbonyl,C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl,amino, C₁-C₄-alkylamino and di-(C₁-C₄-alkyl)amino. Specifically, thesubstituents on the aryl and heteroaryl groups R¹ and R² are selectedfrom the group consisting of fluorine cyano, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl,C₃-C₈-cycloalkyl-C₁-C₆-alkyl, C₃-C₈-halocycloalkyl-C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, formyl, C₁-C₄-alkylcarbonyl,C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl,amino, C₁-C₄-alkylamino and di-(C₁-C₄-alkyl)amino.

The alkenyl group R¹ may be substituted as described above in context ofthe Suzuki reaction for alkenyl groups R¹ and R². In particular, thealkenyl group has a terminal C—C double bond; i.e. Sn is bound to a C—Cdouble bond. This C—C double bond may be substituted as described abovein context of the Suzuki reaction for alkenyl groups R¹ and R². Examplesfor suitable substituents on this C—C double bond or on alkenyl ingeneral are halogen (provided that this not more reactive than the groupZ in the R²—(Z)_(n) compound) cyano, nitro, azido, —SCN, —SF₅, OR¹¹,S(O)_(m)R¹¹, NR^(12a)R^(12b), C(═O)R¹³, C(═S)R¹³, C(═NR^(12a))R¹³,—Si(R¹⁴)₃, alkyl, optionally substituted by one or more radicals R¹⁷;cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, where the 5 last-mentioned substituents may carry oneor more substituents selected from R¹⁵; aryl which may be substituted byone or more radicals R¹⁵, heterocyclyl may be substituted by one or moreradicals R¹⁵; and heteroaryl which may be substituted by one or moreradicals R¹⁵; where R¹¹, R^(12a), R^(12b), R¹³, R¹⁴, R¹⁵ and R¹⁷ are asdefined above in context with the Suzuki reaction. Specifically, thesubstituent on the alkenyl group R¹ is OR¹¹, where R¹³ is alkyl,specifically C₁-C₆-alkyl.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., and specifically from 20° C. to 50° C.

The halogenide, sulfonate or phosphate and the organostannane compoundcan be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7or from 5:1 to 1:5. In case of di- or polyfunctional halogenides,sulfonates or phosphates, the molar ratio relates of course to thenumber of halogenide, sulfonate or phosphate groups in the molecule. Ifn is 1, R²—(Z)_(n) and R¹—Sn(R^(a))₃ are preferably used in a molarratio of from 0.8:1 to 1:2, more preferably from 1:1 to 1:1.5 andspecifically from 1:1 to 1:1.2. If n is 2, R²—(Z)_(n) and R¹—Sn(R^(a))₃are preferably used in a molar ratio of from 0.4:1 to 1:4, morepreferably from 0.5:1 to 1:3 and specifically from 0.5:1 to 1:2.5.

The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g.in an amount of from 0.001 to 0.1 mol per mol of that reactant which isnot used in excess, in particular 0.005 to 0.07 mol per mol of thereactant not used in excess, specifically 0.007 to 0.05 mol per mol ofthe reactant not used in excess. If the reactants are used in equimolarratio, the above amounts of catalyst apply of course to either of thereactants.

The base is generally used in excess, i.e. in overstoichiometric amountswith respect to that reactant not used in excess, e.g. in an amount offrom 1.1 to 5 mol per mol of the reactant not used in excess, inparticular 1.2 to 4 mol per mol of the reactant not used in excess,specifically 1.3 to 2 mol per mol of the reactant not used in excess. Ifthe reactants are used in equimolar ratio, the above amounts of baseapply of course to either of the reactants.

The reaction can be carried out by standard proceedings for Stillereactions, e.g. by mixing all reagents, inclusive catalyst or catalystprecursor and ligand(s) and base, water and the cellulose derivative andreacting them at the desired temperature. Alternatively the reagents canbe added gradually, especially in the case of a continuous orsemicontinuous process.

If the catalyst ligand or any reactant is prone to oxidation by air(such as is the case, for example, for triphenylphosphine,tri(tert-butyl)phosphine, X-Phos,6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphineand several others), the reaction is preferably carried out in an inertatmosphere in order to avoid the presence of oxygen, e.g. under an argonor nitrogen atmosphere. Preferably, moreover, the solvent is used indegassed form. On a laboratory scale this is e.g. obtained by freezing,applying a vacuum and unfreezing under an inert atmosphere or bybubbling a vigorous stream of argon or nitrogen through the solvent orby ultrasonification under an inert atmosphere. On an industrial scaleother methods known in the art can be applied.

Workup proceedings will be described below, as they are similar for mostreactions.

Grubbs Olefin Metathesis

In another particular embodiment the transition metal catalyzed C—Ccoupling reaction is a Grubbs olefin metathesis. Olefin metathesis is anorganic reaction in which fragments of alkenes (olefins) areredistributed by the scission and regeneration of carbon-carbon doublebonds, as illustrated below (the regio- and steric arrangement of thegroups is not necessarily as shown; R^(a) and R^(e) as well as R^(b) andR^(g) can be trans to each other, or an olefinR^(a)R^(d)C═CR^(f)R^(g)+an olefin R^(b)R^(c)C═CR^(e)R^(h) can be formedinstead of the below couple):

Olefin metathesis, which includes i.a. cross metathesis (CM), ringopening metathesis (ROM), ring closing metathesis RCM), acyclic dienemetathesis (ADMET) and ethanolysis, is catalyzed by various transitionmetal catalysts, the most known being the Schrock and Grubbs metathesiscatalysts. In the present case, the olefin metathesis is a Grubbs olefinmetathesis, which means that it is catalyzed by a Grubbs catalyst.Grubbs catalysts are Ruthenium carbene complexes, especially complexesof the following formulae:

First generation Grubbs catalyst:

This first generation catalyst is e.g. prepared from RuCl₂(PPh₃)₄ anddiphenylcyclopropene.

The second generation catalyst has following formula:

The Hoveyda Grubbs first generation catalyst has following formula:

The Hoveyda Grubbs second generation catalyst has following formula:

The Hoveyda Grubbs third generation catalyst has following formula:

Grubbs catalysts in terms of the present invention also include theHoveyda Grubbs I and II analogous catalysts from Zannan Pharma Ltd. witha sulfonamide on the phenyl ring:

In a preferred embodiment, two olefinic compounds R¹R²C═CR³R⁴ andR⁵R⁶C═CR⁷R⁸ are reacted with each other in the presence of a Grubbscatalyst, especially the Grubbs second generation catalyst. R¹, R², R³,R⁴, R⁵, R⁶, R⁷ and R⁸, independently of each other, are hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl,heteroaryl or are one of the substituents listed in context with theSuzuki reaction as suitable radicals on alkyl, alkenyl and alkynylgroups (however except for oxo (═O), ═S and ═NR^(12a)). More precisely,R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸, independently of each other, arehydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl,heterocyclyl, aryl, heteroaryl, halogen, cyano, nitro, azido, —SCN,—SF₅, OR¹¹, S(O)_(m)R¹¹, NR^(12a)R^(12b), C(═O)R¹³, C(═S)R¹³,C(═NR^(12a))R¹³ or —Si(R¹⁴)₃; where R¹¹, R^(12a), R^(12b), R¹³ and R¹⁴are independently as defined above in context with the Suzuki reaction.The alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl orheteroaryl groups R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ can in turn carryone or more substituents. Suitable substituents for the alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl groupscorrespond to those listed above in context with substituents on thealkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling. Suitable substituents for heterocyclylgroups correspond to those listed above in context with substituents onthe aryl or heteroaryl groups R¹ and R² in the Suzuki coupling.

In particular R³, R⁴, R⁷ and R⁸ are hydrogen and at least one of R¹, R²,R⁵ and R⁶ is not hydrogen. More particularly, R³, R⁴, R⁷ and R⁸ arehydrogen, one of R¹ and R² is not hydrogen and one of R⁵ and R⁶ is nothydrogen. In particular, the two radicals not being hydrogen areselected from the group consisting of halogen, cyano, nitro, azido,—SCN, —SF₅, OR¹¹, S(O)_(m)R¹¹, NR^(12a)R^(12b), C(═O)R¹³, C(═S)R¹³,C(═NR^(12a))R¹³, —Si(R¹⁴)₃, alkyl, optionally substituted by one or moreradicals R¹⁷; aryl which may be substituted by one or more radicals R¹⁵,and a 3-, 4-, 5-, 6- 7-, 8-, 9- or 10-membered saturated, partiallyunsaturated or maximally unsaturated (inclusive heteroaromatic)heteromonocyclic or heterobicyclic ring containing 1, 2, 3 or 4heteroatoms or heteroatom groups selected from the group consisting ofN, O, S, NO, SO and SO₂, as ring members, where the heteromonocyclic orheterobicyclic ring may be substituted by one or more radicals R¹⁵;where R¹¹, R^(12a), R^(12b), R¹³, R¹⁴, R¹⁵ and R¹⁷ are as defined abovein context with the Suzuki reaction. Specifically, one of R¹ and R² isalkyl, optionally substituted by one or more radicals R¹⁷; and one of R⁵and R⁶ is C(═O)R¹³. More specifically one of R¹ and R² is C₁-C₄-alkylsubstituted with an aryl group which may carry one or more substituentsR¹⁵ as defined in context with the Suzuki reaction, and one of R⁵ and R⁶is C(═O)R¹³, where R¹³ is C₁-C₆-alkoxy.

The olefins R¹R²C═CR³R⁴ and R⁵R⁶C═CR⁷R⁸ are used in a molar ratio offrom 10:1 to 1:10, e.g. from 7:1 to 1:7 or 5:1 to 1:5, preferably 4:1 to1:4, in particular 3:1 to 1:3 and specifically from 2:1 to 1:2.

The catalyst is generally used in catalytic, i.e. substoichiometricamounts, e.g. in an amount of from 0.0001 to 0.1 mol per mol of thatreactant which is not used in excess, in particular 0.001 to 0.05 molper mol of the reactant not used in excess, specifically 0.002 to 0.01mol per mol of the reactant not used in excess. If the reactants areused in equimolar ratio, the above amounts of catalyst apply of courseto either of the reactants.

It may be advantageous to carry out the reaction in the presence of aweak acid, such as acetic acid, citric acid, malic acid, oxalic acid orsuccinic acid. The acid is generally used in substoichiometric amounts,e.g. in an amount of from 0.0001 to 0.1 mol per mol of that reactantwhich is not used in excess, in particular 0.001 to 0.05 mol per mol ofthe reactant not used in excess, specifically 0.002 to 0.01 mol per molof the reactant not used in excess. If the reactants are used inequimolar ratio, the above amounts of acid apply of course to either ofthe reactants.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 20° C. to 50° C. andvery specifically from 20° C. to 30° C.

The reaction can be carried out by standard proceedings for olefinmetathesis reactions, e.g. by mixing all reagents, inclusive catalyst,water and the cellulose derivative and reacting them at the desiredtemperature. Alternatively the reagents can be added gradually,especially in the case of a continuous or semicontinuous process.

Although Grubbs catalysts are rather stable to oxidation by air, thereaction is nevertheless preferably carried out in an inert atmosphere.Preferably, moreover, the solvent is used in degassed form. On alaboratory scale this is e.g. obtained by freezing, applying a vacuumand unfreezing under an inert atmosphere or by bubbling a vigorousstream of argon or nitrogen through the solvent or by ultrasonificationunder an inert atmosphere. On an industrial scale other methods known inthe art can be applied.

Workup proceedings will be described below, as they are similar for mostreactions.

1,4-Additions of an Organoborane Compounds to α,β-olefinicallyUnsaturated Carbonyl Compounds

In another particular embodiment the transition metal catalyzed C—Ccoupling reaction is a 1,4-addition of an organoborane compound to anα,β-olefinically unsaturated carbonyl compound. This addition reactionresembles the well-known Michael addition, uses however an organoboroncompound as nucleophile instead of a CH-acidic compound, and usestransition metal catalysis. Suitable catalysts are Pd, Ru and especiallyRh catalysts.

Preferably, the organoboron compound is a compound of formula R¹—BY₂,where R¹ is an alkyl, alkenyl, alkynyl, aryl or heteroaryl group and Yis an alkyl, O-alkyl or hydroxyl group, or the two substituents Y formtogether with the boron atom they are bound to a mono-, bi- orpolycyclic ring; or the organoboron compound is a compound of formulaR¹—BF₃M, where M is a metal equivalent. Examples of suitable organoboroncompounds R¹—BY₂ are R¹—B(OH)₂, R¹—B(O—C₁-C₄-alkyl)₂,R¹—B(C₁-C₄-alkyl)₂, or the MIDA ester of R¹—B(OH)₂(MIDA=N-methyliminodiacetic acid; HO—C(═O)—CH₂—N(CH₃)—CH₂—C(═O)—OH; i.e.the two Y form together —O—C(═O)—CH₂—N(CH₃)—CH₂—C(═O)—O—).

The α,β-olefinically unsaturated carbonyl compound is preferably acompound of formula R²R³C═CR⁴—C(═O)—R⁵, where R², R³ and R⁴,independently of each other, are hydrogen, alkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl and R⁵ is hydrogen, alkyl, cycloalkyl,aryl, heteroaryl, OH, SH, alkoxy, alkylthio, NH₂, alkylamino ordialkylamino. The alkyl (also as part of alkoxy, alkylthio, alkylaminoor dialkylamino), alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl orheteroaryl groups R¹, R², R³, R⁴ and R⁵ can carry one or moresubstituents. Suitable substituents for the alkyl, alkenyl, alkynyl,cycloalkyl, aryl and heteroaryl groups correspond to those listed abovein context with substituents on the alkyl, alkenyl, alkynyl, cycloalkyl,aryl or heteroaryl groups R¹ and R² in the Suzuki coupling. Suitablesubstituents for heterocyclyl groups correspond to those listed above incontext with substituents on the cycloalkyl, aryl or heteroaryl groupsR¹ and R² in the Suzuki coupling.

In these substituents, however, all functional groups have to be lessreactive towards the organoboron compound than the desired reaction siteon the C—C double bond of the α,β-olefinically unsaturated carbonylcompound.

Reaction of the organoboron compound with R²R³═CR—C(═O)—R⁵ yields acompound R¹—(R²)(R)³C—CHR⁴—C(═O)—R⁵.

Specifically R¹ is an aryl or heteroaryl group which may be substitutedas described above in context with the Suzuki reaction.

In a particular embodiment the aryl group R¹ is mono-, bi- or tricyclicand is specifically selected from the group consisting of phenyl andnaphthyl; and the heteroaryl group R¹ is in particular mono-, bi- ortricyclic and is specifically selected from the group consisting of 5-or 6-membered heteroaromatic monocyclic rings and 9- or 10-memberedheteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members. Mono-or bicyclic aryl or heteroaryl groups R are for example phenyl,naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl,isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl,[1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls,pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl,isoquinolinyl, quinazalinyl and the like. More particularly, they arefor example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl,1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl,1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl,1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl,1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl,4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl,1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl,1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl,indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromaticbicyclic rings shown below in the “general definitions”.

The aryl and heteroaryl groups R¹ can carry one or more substituents,e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2substituents. Suitable substituents are listed above in context witharyl and heteroaryl groups R¹ and R² in the Suzuki reaction. In aparticular embodiment, the substituents on the aryl and heteroarylgroups R¹ are selected from the group consisting of fluorine, cyano,nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, Oand S as ring members and a 9- or 10-membered heteroaromatic bicyclicring containing 1, 2, 3 or 4 heteroatoms selected from the groupconsisting of N, O and S as ring members, where phenyl and theheteroaromatic rings may carry one or more substituents selected fromthe group consisting of fluorine, cyano, nitro, OH, SH, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl, C₂-C₆-alkynyl,C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, formyl, C₁-C₄-alkylcarbonyl,C₁-C₄-haloalkycarbonyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl,amino, C₁-C₄-alkylamino and di-(C₁-C₄-alkyl)amino. Specifically, thesubstituents on the aryl and heteroaryl groups R¹ are selected from thegroup consisting of fluorine, cyano, C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino.

In particular at least one of R² and R³ is H. If one of R² and R³ is notH, this is specifically alkyl. Specifically, R⁴ is H. Specifically R⁵ isalkoxy.

Suitable Pd catalysts correspond to those mentioned above in contextwith the Suzuki reaction.

Like Pd, Rh may be introduced as a salt into the reaction and convertedin situ into a complex by reaction with suitable ligands. It is howevermore expedient to use preformed Rh catalysts.

Suitable Rh catalysts are e.g. [RhCl(C₂H₄)₂]₂, [RhCl₂(C₂H₄)₂],[Rh(nbd)]₂BF₄ (nbd=norbornadiene), [Rh(nbd)]₂CF₃SO₃,[Rh(cod)(CH₃CN)₂]BF₄ (cod=cyclooctadiene), [Rh(cod)₂]PF₆,[Rh(cod)₂]SbF₆, [Rh(cod)₂]BF₄, [Rh(cod)₂]CF₃SO₃, [Rh(OH)(cod)]₂,acetylacetonatobis(ethylene)rhodium(I),(acetylacetonato)(1,5-cyclooctadiene)rhodium(I),(acetylacetonato)dicarbonylrhodium(I),(acetylacetonatoxnorbornadiene)rhodium(I),(bicyclo[2.2.1]hepta-2,5-diene)[1,4-bis(diphenylphosphino)butane]rhodium(I)tetrafluoroborate, bicyclo[2.2.1]hepta-2,5-diene-rhodium(I) chloridedimer, [(bisacetonitrile)(norbornadiene)]rhodium(I)hexafluoroantimonate,bis(2,2-dimethylpropanoato)(4-methylphenyl)bis[tris[4-(trifluoromethyl)phenyl]phosphine]rhodium,[1,4-bis(diphenylphosphino)butane](1,5-cyclooctadiene)rhodium(I)tetrafluoroborate, bis(triphenylphosphine)rhodium(I) carbonyl chloride,chlorobis(cyclooctene)rhodium(I) dimer, and the like.

The organoboron compound and the unsaturated carbonyl compound can beused in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from5:1 to 1:5. The organoboron compounds are however generally used in atleast equimolar amount, e.g. from equimolar amount to a fivefold or inparticular threefold or especially twofold or 1.5-fold excess. Ifhowever the carbonyl compound is more easily available and/or lessexpensive than the organoboron compound, this can instead be used inexcess, e.g. in a fivefold or threefold or twofold or 1.5-fold excess.Especially in case that the organoboron compound is a MIDA ester, theorganoboron compound and the carbonyl compound can be used inapproximately equimolar amounts.

The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g.in an amount of from 0.001 to 0.1 mol per mol of that reactant which notused in excess (here mostly the α,β-olefinically unsaturated carbonylcompound), in particular 0.005 to 0.07 mol per mol of the reactant notused in excess, specifically 0.01 to 0.07 mol per mol of the reactantnot used in excess. If the reactants are used in equimolar ratio, theabove amounts of catalyst apply of course to either of the reactants.

The reaction can be carried out by standard proceedings for transitionmetal-catalyzed 1,4-coupling reactions, e.g. by mixing all reagents,inclusive catalyst or catalyst precursor and ligand(s), water and thecellulose derivative and reacting them at the desired temperature.Alternatively the reagents can be added gradually, especially in thecase of a continuous or semicontinuous process.

If the catalyst ligand or any reactant is prone to oxidation by air, thereaction is preferably carried out in an inert atmosphere in order toavoid the presence of oxygen, e.g. under an argon or nitrogenatmosphere. Preferably, moreover, the solvent is used in degassed form.On a laboratory scale this is e.g. obtained by freezing, applying avacuum and unfreezing under an inert atmosphere or by bubbling avigorous stream of argon or nitrogen through the solvent or byultrasonification under an inert atmosphere. On an industrial scaleother methods known in the art can be applied.

Workup proceedings will be described below, as they are similar for mostreactions.

Cyclopropanation

In another particular embodiment the transition metal catalyzed C—Ccoupling reaction is a cyclopropanation. Cyclopropanations withouttransition metal catalysis are also well-known reactions, but in thiscontext, only transition metal catalyzed cyclopropanations arediscussed. As said, in a transition metal catalyzed cyclopropanation anolefinically unsaturated compound is reacted with a diazo compound to acyclopropane in the presence of a transition metal catalyst. Theolefinically unsaturated compound is preferably a compound of formulaR¹R²C═CR³R⁴, and the diazo compound is preferably a compound of formulaN₂═CR⁵R⁶; where R¹, R², R³, R⁴, R⁵ and R⁶, independently of each other,are selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, hetaryl,halogen, cyano, nitro, azido, —SCN, —SF₅, OR¹¹, S(O)_(m)R¹¹,NR^(12a)R^(12b), C(═O)R¹³, C(═S)R¹³, C(═NR^(12a))R¹³ and —Si(R¹⁴)₃;where R¹¹, R^(12a), R^(12b), R¹³ and R¹⁴ are independently as definedabove in context with the Heck reaction; where the alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl andheteroaryl groups R¹, R², R³, R⁴, R⁵ and R⁶ can carry one or moresubstituents. Suitable substituents for the alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, heterocyclyl, aryl and heteroaryl groups correspond tothose listed above in context with substituents on the alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl groupsR¹ and R² in the Suzuki coupling. Suitable substituents for heterocyclylgroups correspond to those listed above in context with substituents onthe cycloalkyl, aryl or heteroaryl groups R¹ and R² in the Suzukicoupling. Specifically, the cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl, heterocyclyl andheteroaryl groups R¹, R², R³ and R⁴ may be substituted by one or moreradicals R¹⁵.

Suitable catalysts are all those customarily used for cyclopropanations,such as the following copper(II) complexes of Schiff's bases

or the above-described semicorrin, bisoxazolin or porphyrin complexes.Among the above semicorrin and bis-oxazolin complexes, preference isgiven to following complexes of copper:

L is a simple ligand, such as Cl, or two L form together a usualbidentate ligand, such as acetylacetonate or methyl acetylacetate.

Preferably however, porphyrin complexes are used, in particularporphyrin complexes with Fe, Ru, Rh or Ir as central metal, but Zn mayalso be used.

The porphyrin ligand has preferably following structure:

Generally, at least one of R^(a), R^(b), R^(c) and R^(d) is an aromaticgroup, such as phenyl, optionally substituted by 1, 2 or 3 substituentsselected from the group consisting of methyl, methoxy, hydroxyl, aminoand the like. For sterically selective reactions, expediently, at leastone of R^(a), R^(b), R^(c) and R^(d) is a chiral group, such as a BINAPradical, a phenyl ring carrying one or more chiral substituents or aphenyl ring fused to one or more rings resulting in a chiral system.Radicals R^(a), R^(b), R^(c) and R^(d) which are not an aromatic groupare generally selected from the group consisting of alkyl groups, alkoxygroups, alkyl carbonyl groups and alkoxycarbonyl groups. They canhowever also be hydrogen. In a specific embodiment, R^(a), R^(b), R^(c)and R^(d) are phenyl, and the central atom is Fe, in particular Fe(III).The charge of the central metal is generally neutralized by a halide,especially chloride, an acetate or other anions customary in suchcomplexes.

In a particular embodiment, in the olefinically unsaturated compoundR¹R²C═CR³R⁴ the radicals R¹, R², R³ and R⁴ are not electron-withdrawinggroups and are preferably selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl,heterocyclyl, aryl and hetaryl, where these groups (apart from hydrogen,of course) may be substituted as described above. Specifically, thepresent method relates to a cyclopropanation reaction wherein in theolefinically unsaturated compound R¹R²C═CR³R⁴ in two or three of R¹, R²,R³ and R⁴ are hydrogen and the other is/are C₁-C₄-alkyl,C₃-C₆-cycloalkyl or aryl, specifically phenyl, where the alkyl,cycloalkyl and aryl radical may carry one or more substituents. Suitablesubstituents correspond to those listed above in context withsubstituents on the alkyl, cycloalkyl or aryl groups R¹ and R² in theSuzuki coupling. Very specifically, three of R¹, R², R³ and R⁴ arehydrogen and the other is phenyl which may be substituted as describedabove, specific substituents being selected from the group consisting ofCN, halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy, C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl and phenyl.

In the diazo compound N₂═CR⁵R⁶, R⁵ is specifically H and R⁶ is aC₁-C₄-alkoxycarbonyl group.

The diazocompound is prepared by known means, such as reaction of theC₁-C₄-alkyl ester of glycine with a nitrite, generally sodium nitrite,often in the presence of an acid. Suitable acids are inorganic acidswhich do not interfere with the diazonium formation, such ashydrochloric acid, and organic acids, such as acetic acid,trifluoroacetic acid, toluene sulfonic acid and the like. The diazocompound can be prepared in situ before the olefinic compound is added,i.e. in the aqueous solvent used in the method of the invention in thepresence of the cellulose derivative, or, preferably, in the presence ofthe olefinic compound. For example, the olefinic compound, theC₁-C₄-alkyl ester of glycine, the transition metal catalyst, if desiredthe acid, water and the cellulose derivative are mixed and sodiumnitrite is added. If desired, the reaction mixture can be heated before,during or after addition of sodium nitrite, e.g. to 30 to 60° C. or 35to 50° C. or to 35 to 45° C.

The diazo compound is generally used in at least equivalent amounts,preferably in excess, with respect to the olefinic compound, the molarratio of diazo compound and olefinic compound being preferably of from1:1 to 10:1, in particular from 1.1:1 to 5:1 and specifically from 1.5:1to 3:1.

The nitrite is generally used in at least equivalent amounts, often inslight excess, with respect to the diazo compound, the molar ratio ofnitrite and diazo compound being preferably of from 1:1 to 5:1, inparticular from 1:1 to 2:1 and specifically from 1.1:1 to 1.5:1.

The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g.in an amount of from 0.001 to 0.1 mol per mol of that reactant which notused in excess (here mostly the olefinic compound), in particular 0.005to 0.07 mol per mol of the reactant not used in excess, specifically0.005 to 0.05 mol per mol of the reactant not used in excess. If thereactants are used in equimolar ratio, the above amounts of catalystapply of course to either of the reactants.

Workup proceedings will be described below, as they are similar for mostreactions.

b) C—N Coupling Reactions

In a particular embodiment, the transition metal catalyzed reaction is aC—N coupling reaction. Transition metal catalyzed C—N coupling reactionsare well known. Examples are the Buchwald-Hartwig reaction andAu-catalyzed cyclodehydratizations of alkynes carrying in α-position tothe alkyne group an OH group and in β-position a primary or secondaryamino group to give pyrroles.

Buchwald-Hartwig Reaction

In a particular embodiment the transition metal catalyzed C—N couplingreaction is a Buchwald-Hartwig reaction. The Buchwald-Hartwig reactionis a transition metal-catalyzed, mostly a Pd catalyzed, C—N or C—O bondformation between an aryl or heteroaryl halogenide or sulfonate and aprimary or secondary amine, carboxamide, sulfonamide, imide, urea orurethane (for C—N bond formation) or an alcohol (for C—O bondformation), generally in the presence of a base. In context with C—Ncoupling reactions, the Buchwald-Hartwig reaction is understood as atransition metal-catalyzed, mostly a Pd catalyzed, C—N bond formationbetween an aryl or heteroaryl halogenide or sulfonate (the sulfonatebeing in particular a fluorinated alkylsulfonate or tosylate,specifically triflate or nonaflate) and a primary or secondary amine,carboxamide, sulfonamide, imide, urea or urethane, generally in thepresence of a base.

Preferably, a halogenide or sulfonate R²—(Z)_(n), where R² is an aryl orheteroaryl group, Z is a halogenide or sulfonate group (the sulfonatebeing in particular a fluorinated alkylsulfonate or tosylate,specifically triflate or nonaflate) and n is 1, 2, 3 or 4, is reactedwith a compound H—N(R¹)R³, where R¹ is H, alkyl, alkenyl, alkapolyenyl,alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl,heterocyclyl, heteroaryl or —C(O)—R⁴, and R³ is H, alkyl, alkenyl,alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, aryl, heterocyclyl, heteroaryl, —C(O)—R⁴, —S(O)₂—R⁴,—C(O)—O—R⁴ or —C(O)—N(R⁴)R⁵, where R⁴ and R⁵ are independently H, alkyl,alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl,cycloalkyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl,heterocyclyl or heteroaryl, or R⁴ and R⁵ form together with the nitrogenatom they are bound to a mono- bi- or polycyclic heterocyclic ring; orR¹ and R³ form together with the nitrogen atom they are bound to amono-, bi- or polycyclic heterocyclic ring. The reaction of thehalogenide or sulfonate R²—(Z)_(n) and the amine (derivative) H—N(R¹)R³yields a compound (R³(R¹)N)_(n)—R². The aryl or heteroaryl halide orsulfonate can contain more than one halide or sulfonate group (when n is2, 3 or 4), so that multiply coupled compounds can form, especially ifthe amine compound is used in excess. For instance, a difunctionalcompound R²—(Z)₂ can yield a twofold C—N coupled compoundR³(R¹)N—R²—N(R¹)R³.

Due to the tolerance of the Buchwald-Hartwig reaction to a wide varietyof functional groups, the alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl,heterocyclyl, aryl or heteroaryl groups R¹, R², R³, R⁴, and R⁵, as wellas the mono- bi- or polycyclic heterocyclic ring formed by R⁴ and R⁵ orR¹ and R³ together with the nitrogen atom they are bound to, can carryone or more substituents. Suitable substituents for alkyl, alkenyl,alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, aryl and heteroaryl correspond to those listed above incontext with substituents on the alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl orheteroaryl groups R¹ and R² in the Suzuki coupling. Suitablesubstituents for heterocyclyl groups and for the mono- bi- or polycyclicheterocyclic ring formed by R⁴ and R⁵ together with the nitrogen atomthey are bound to or by R¹ and R³ together with the nitrogen atom theyare bound to correspond to those listed above in context withsubstituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling.

In these substituents, however, all functional groups, especiallyhalogen atoms and sulfonyloxy groups, have to be less reactive than thehalogen atom or sulfonate group on the desired reaction site of theR²—(Z)_(n) compound; amino groups have to be less reactive than theamino group on the desired reaction site of the H—N(R¹)R³ compound.

Suitable Pd catalysts (inclusive ligands) are those mentioned above incontext with the Suzuki coupling.

Suitable bases are those mentioned above in context with the Suzukicoupling.

Specifically, the present method relates to a Buchwald-Hartwig reactionin which an aromatic or heteroaromatic halogenide R²—(Z)_(n), where R²is an optionally substituted mono-, bi- or polycyclic aryl or heteroarylgroup, Z is a halogen atom, especially Cl, Br or I, and n is 1, isreacted with an amine (derivative) H—N(R¹)R³, where R¹ is H and R³ isoptionally substituted alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, —C(O)—R⁴, —S(O)₂—R⁴, —C(O)—O—R⁴ or—C(O)—N(R⁴)R⁵, where R⁴ and R⁵ are independently of each other alkyl,optionally substituted aryl or optionally substituted heteroaryl, or R⁴and R⁵ form together with the nitrogen atom they are bound to amonocyclic heterocyclic ring, in the presence of a Pd catalyst,specifically of a Pd catalyst with cBRIDP or t-BuXPhos as ligand, and inthe presence of a base, specifically of an alkali metal alcoholate,especially an alkali metal tert-butanolate, or a silanolate, especiallyan alkali metal triisopropylsilanolate.

In a particular embodiment the aryl groups R¹, R², R³, R⁴, and R⁵ aremono-, bi- or tricyclic and are specifically selected from the groupconsisting of phenyl and naphthyl; and the heteroaryl groups R¹, R², R³,R⁴, and R⁵ are in particular mono-, bi- or tricyclic and arespecifically selected from the group consisting of 5- or 6-memberedheteroaromatic monocyclic rings and 9- or 10-membered heteroaromaticbicyclic rings containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members. Mono- or bicyclic arylor heteroaryl groups R¹, R², R³, R⁴, and R⁵ are are for example phenyl,naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl,isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl,[1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls,pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl,isoquinolinyl, quinazalinyl and the like. More particularly, they arefor example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl,1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl,1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl,1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl,1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl,4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl,1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl,1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl,indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromaticbicyclic rings shown below in the “general definitions”.

The aryl and heteroaryl groups R¹, R², R³, R⁴, and R⁵ can carry one ormore substituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3,specifically 1 or 2 substituents. Suitable substituents are listed abovein context with aryl and heteroaryl groups R¹ and R² in the Suzukireaction. In a particular embodiment, the substituents on the aryl andheteroaryl groups R¹, R², R³R⁴, and R⁵ are selected from the groupconsisting of fluorine, cyano, nitro, OH, SH, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl, C₂-C₆-alkynyl,C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl,C₃-C₈-cycloalkyl-C₁-C₆-alkyl, C₃-C₈-halocycloalkyl-C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, formyl, C₁-C₄-alkylcarbonyl,C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl,phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1,2, 3 or 4 heteroatoms selected from the group consisting of N, O and Sas ring members and a 9- or 10-membered heteroaromatic bicyclic ringcontaining 1, 2, 3 or 4 heteroatoms selected from the group consistingof N, O and S as ring members, where phenyl and the heteroaromatic ringsmay carry one or more substituents selected the group consisting of fromfluorine, cyano, nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₂-C₆-alkenyl, C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl,C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino. Specifically, the substituents on the aryl andheteroaryl groups R¹, R², R³, R⁴, and R⁵ are selected from the groupconsisting of fluorine, cyano, C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl andC₁-C₄-haloalkoxycarbonyl.

In a more specific embodiment an aromatic or heteroaromatic halogenideR²—(Z)_(n), where

R² is a mono- or bicyclic aryl group (i.e. phenyl or naphthyl) or is a5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4heteroatoms selected from the group consisting of N, O and S as ringmembers, where the mono- or bicyclic aryl group and the heteroaromaticmonocyclic ring may carry 1, 2 or 3 substituents selected from the groupconsisting of C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl andC₁-C₄-haloalkoxycarbonyl,Z is a halogen atom, especially Cl, Br or I, andn is 1,is reacted with an amine (derivative) H—N(R¹)R³, whereR¹ is H andR³ is optionally substituted C₁-C₆-alkyl, a mono- or bicyclic aryl group(i.e. phenyl or naphthyl), a 5- or 6-membered heteroaromatic monocyclicring containing 1, 2, 3 or 4 heteroatoms selected from the groupconsisting of N, O and S as ring members, where the mono- or bicyclicaryl group and the heteroaromatic monocyclic ring may carry 1, 2 or 3substituents selected from the group consisting of C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, formyl, C₁-C₄-alkylcarbonyl,C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl andC₁-C₄-haloalkoxycarbonyl; —C(O)—R⁴, —S(O)₂—R⁴, —C(O)—O—R⁴ or—C(O)—N(R⁴)R⁵, where the optional substituents on C₁-C₆-alkyl areselected from the group consisting of a mono- or bicyclic aryl group(i.e. phenyl or naphthyl) and a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members, where the mono- orbicyclic aryl group and the heteroaromatic monocyclic ring may carry 1,2 or 3 substituents selected from the group consisting of C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, formyl, C₁-C₄-alkylcarbonyl,C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl andC₁-C₄-haloalkoxycarbonyl; andR⁴ and R⁵ are independently of each other hydrogen, C₁-C₆-alkyl, a mono-or bicyclic aryl group (i.e. phenyl or naphthyl) or a 5- or 6-memberedheteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members, wherethe mono- or bicyclic aryl group and the heteroaromatic monocyclic ringmay carry 1, 2 or 3 substituents selected from the group consisting ofC₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl,C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, formyl, C₁-C₄-alkylcarbonyl,C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl andC₁-C₄-haloalkoxycarbonyl; or R⁴ and R⁵ form together with the nitrogenatom they are bound to a 3-, 4-, 5-, 6- or 7-membered monocyclicsaturated heterocyclic ring,in the presence of a Pd catalyst, specifically of a Pd catalyst withcBRIDP or t-BuXPhos as ligand, and in the presence of a base,specifically of an alkali metal alcoholate, especially an alkali metaltert-butanolate, or a silanolate, especially an alkali metaltriisopropylsilanolate.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 20° C. to 50° C.

The halogenide or sulfonate and the amine (derivative) can be used in amolar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to1:5. In case of di- or polyfunctional halides or sulfonates, the molarratio relates of course to the number of halide or sulfonate groups inthe molecule. If n is 1, R²—(Z)_(n) and H—N(R¹)R³ are preferably used ina molar ratio of from 3:1 to 1:3, in particular from 2:1 to 1:2. If n is2, R²—(Z)_(n) and H—N(R¹)R³ are preferably used in a molar ratio of from1.5:1 to 1:6, more preferably from 1:1 to 1:4. Specifically, the amine(derivative) H—N(R¹)R³ is used in slight excess, e.g. in a 2-fold or1.5-fold or 1.2-fold excess with respect to the n groups Z.

The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g.in an amount of from 0.001 to 0.5 mol per mol of that reactant which isnot used in excess, in particular 0.002 to 0.3 mol per mol of thereactant not used in excess, specifically 0.003 to 0.2, morespecifically 0.005 to 0.1 mol per mol of the reactant not used inexcess. If the reactants are used in equimolar ratio, the above amountsof catalyst apply of course to either of the reactants.

The base is generally used in at least equimolar amount and mostly inexcess, i.e. in overstoichiometric amounts, with respect to thatreactant not used in excess, e.g. in an amount of from 1 to 5 mol permol of the reactant not used in excess, in particular 1.2 to 3 mol permol of the reactant not used in excess, specifically 1.3 to 2 mol permol of the reactant not used in excess. If the reactants are used inequimolar ratio, the above amounts of base apply of course to either ofthe reactants.

The reaction can be carried out by standard proceedings forBuchwald-Hartwig reactions, e.g. by mixing all reagents, inclusivecatalyst or catalyst precursor and ligand(s) and base, water and thecellulose derivative and reacting them at the desired temperature.Alternatively the reagents can be added gradually, especially in thecase of a continuous or semicontinuous process.

If the catalyst ligand or any reactant is prone to oxidation by air(such as is the case, for example, for triphenylphosphine,tri(tert-butyl)phosphine, X-Phos,6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphineand several others), the reaction is preferably carried out in an inertatmosphere in order to avoid the presence of oxygen, e.g. under an argonor nitrogen atmosphere. Preferably, moreover, the solvent is used indegassed form. On a laboratory scale this is e.g. obtained by freezing,applying a vacuum and unfreezing under an inert atmosphere or bybubbling a vigorous stream of argon or nitrogen through the solvent orby ultrasonification under an inert atmosphere. On an industrial scaleother methods known in the art can be applied.

Workup proceedings will be described below, as they are similar for mostreactions.

Au-Catalyzed Cyclodehydratizations of Aminoalcohols

α,β-amino alcohols containing an appropriately positioned alkynylresidue (C—C triple bond) can undergo gold-catalyzed ringclosure/dehydration (cyclodehydration). For instance, an alkyne carryingin α-position to the alkyne group an OH group and in β-position aprimary or secondary amino function undergoes cyclodehydration to thecorresponding pyrrole, as shown in the scheme below; an alkyne carryingin β-position to the alkyne group an OH group and in γ-position aprimary or secondary amino function undergoes cyclodehydration to thecorresponding dihydropyridine, etc.

R¹, R², R³ and R⁴ are independently of each other H, alkyl, cycloalkyl,aryl, heterocyclyl or heteroaryl.

The alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl groups R¹, R²,R³ and R⁴ can carry one or more substituents. Suitable substituents foralkyl, cycloalkyl, aryl and heteroaryl correspond to those listed abovein context with substituents on the alkyl, cycloalkyl, aryl orheteroaryl groups R¹ and R² in the Suzuki coupling. Suitablesubstituents for heterocyclyl groups correspond to those listed above incontext with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl,mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroarylgroups R¹ and R² in the Suzuki coupling.

In a specific embodiment, R² and R³ are H, alkyl, cycloalkyl, inparticular alkyl, specifically C₁-C₆-alkyl, and R¹ is aryl orheteroaryl, where aryl and heteroaryl may carry one or moresubstituents. Suitable substituents correspond to those listed above incontext with aryl or heteroaryl groups R¹ and R² in the Suzuki coupling.

In a particular embodiment the aryl group R¹ is mono-, bi- or tricyclicand is specifically selected from the group consisting of phenyl andnaphthyl; and the heteroaryl group R¹ is in particular mono-, bi- ortricyclic and is specifically selected from the group consisting of 5-or 6-membered heteroaromatic monocyclic rings and 9- or 10-memberedheteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members. Mono-or bicyclic aryl or heteroaryl groups R are for example phenyl,naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl,isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl,[1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls,pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl,isoquinolinyl, quinazalinyl and the like. More particularly, they arefor example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl,1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl,1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,3,5-oxadiazol-3-yl,1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl,1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl,4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl,1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl,1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl,indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromaticbicyclic rings shown below in the “general definitions”.

The aryl and heteroaryl groups R¹ can carry one or more substituents,e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2substituents. Suitable substituents are listed above in context witharyl and heteroaryl groups R¹ and R² in the Suzuki reaction. In aparticular embodiment, the substituents on the aryl and heteroarylgroups R¹ are selected from the group consisting of halogen, cyano,nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members and a 9- or 10-memberedheteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members, wherephenyl and the heteroaromatic rings may carry one or more substituentsselected from the group consisting of halogen, cyano, nitro, OH, SH,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino. Specifically, the substituents on the aryl andheteroaryl groups R¹ are selected from the group consisting of halogen,cyano, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino.

Suitable Au catalysts are Au(III) salts and Au complexes. Examples forsuitable Au salts are AuCl₃, AuBr₃ or Au(triflate)₃. Suitable complexesare for example (Ph₃P)AuCl, [c-Hex₂(o-biphenyl)]PAuCl or[t-Bu₂(o-biphenyl)]PAuCl.

Ag salts or complexes can be use as co-catalysts. Examples are Ag(I)triflate or AgNO₃.

The Au catalyst is used in catalytic, i.e. substoichiometric amounts,e.g. in an amount of from 0.001 to 0.5 mol per mol of aminoalcohol, inparticular 0.005 to 0.2 mol per mol of aminoalcohol, specifically 0.005to 0.1 per mol of aminoalcohol, more specifically 0.01 to 0.05 mol permol of aminoalcohol.

Also the Ag co-catalyst is used in catalytic, i.e. substoichiometricamounts, e.g. in an amount of from 0.001 to 0.5 mol per mol ofaminoalcohol, in particular 0.005 to 0.2 mol per mol of aminoalcohol,specifically 0.005 to 0.1 per mol of aminoalcohol, more specifically0.01 to 0.05 mol per mol of aminoalcohol.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 20° C. to 50° C.

The reaction can be carried out, e.g., by mixing all reagents, inclusivecatalyst or catalyst precursor and ligand(s), water and the cellulosederivative and reacting them at the desired temperature. Alternativelythe reagents can be added gradually, especially in the case of acontinuous or semicontinuous process.

If the catalyst ligand or any reactant is prone to oxidation by air, thereaction is preferably carried out in an inert atmosphere in order toavoid the presence of oxygen, e.g. under an argon or nitrogenatmosphere. Preferably, moreover, the solvent is used in degassed form.On a laboratory scale this is e.g. obtained by freezing, applying avacuum and unfreezing under an inert atmosphere or by bubbling avigorous stream of argon or nitrogen through the solvent or byultrasonification under an inert atmosphere. On an industrial scaleother methods known in the art can be applied.

Workup proceedings will be described below, as they are similar for mostreactions.

c) C—O Coupling Reactions

In a particular embodiment, the transition metal catalyzed reaction is aC—O coupling reaction. Transition metal catalyzed C—O coupling reactionsare well known. Examples are Au-catalyzed cyclodehydratizations ofalkyne diols, cyclizations of alkynenols, of alkynones or of allenonesor the formation of alcohols or ethers via C—O coupling in analogy tothe Ullmann biaryl ether synthesis.

Au-Catalyzed Cyclodehydratizations of Diols

α,β-diols containing an appropriately positioned alkynyl residue (C—Ctriple bond) can undergo gold-catalyzed ring closure/dehydration(cyclodehydration). For instance, an alkyne carrying in α- andβ-position to the alkyne group two OH groups undergoes cyclodehydrationto the corresponding furane, as shown in the scheme below; an alkynecarrying in β- and γ-position to the alkyne group two OH groupsundergoes cyclodehydration to the corresponding pyrane, etc.

R¹, R² and R³ are independently of each other H, alkyl, cycloalkyl,aryl, heterocyclyl or heteroaryl.

The alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl groups R¹, R²and R³ can carry one or more substituents. Suitable substituents foralkyl, cycloalkyl, aryl and heteroaryl correspond to those listed abovein context with substituents on the alkyl, cycloalkyl, aryl orheteroaryl groups R¹ and R² in the Suzuki coupling. Suitablesubstituents for heterocyclyl groups correspond to those listed above incontext with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl,mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroarylgroups R¹ and R² in the Suzuki coupling.

In a specific embodiment, R² and R³ are H, alkyl or cycloalkyl, inparticular alkyl, specifically C₁-C₆-alkyl, and R¹ is aryl orheteroaryl, where aryl and heteroaryl may carry one or moresubstituents. Suitable substituents correspond to those listed above incontext with aryl or heteroaryl groups R¹ and R² in the Suzuki coupling.

In a particular embodiment the aryl group R¹ is mono-, bi- or tricyclicand is specifically selected from the group consisting of phenyl andnaphthyl; and the heteroaryl group R¹ is in particular mono-, bi- ortricyclic and is specifically selected from the group consisting of 5-or 6-membered heteroaromatic monocyclic rings and 9- or 10-memberedheteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members. Mono-or bicyclic aryl or heteroaryl groups R¹ are for example phenyl,naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl,isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl,[1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls,pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl,isoquinolinyl, quinazalinyl and the like. More particularly, they arefor example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl,1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl,1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl,1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl,1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl,4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl,1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl,1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl,indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromaticbicyclic rings shown below in the “general definitions”.

The aryl and heteroaryl groups R¹ can carry one or more substituents,e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2substituents. Suitable substituents are listed above in context witharyl and heteroaryl groups R¹ and R² in the Suzuki reaction. In aparticular embodiment, the substituents on the aryl and heteroarylgroups R¹ are selected from the group consisting of halogen, cyano,nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members and a 9- or 10-memberedheteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members, wherephenyl and the heteroaromatic rings may carry one or more substituentsselected from the group consisting of halogen, cyano, nitro, OH, SH,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino. Specifically, the substituents on the aryl andheteroaryl groups R¹ are selected from the group consisting of halogen,cyano, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino.

Suitable Au catalysts are Au(III) salts and Au complexes. Examples forsuitable Au salts are AuCl₃, AuBr₃ or Au(triflate)₃. Suitable complexesare for example (Ph₃P)AuCl, [c-Hex₂(o-biphenyl)]PAuCl or[t-Bu₂(o-biphenyl)]PAuCl.

Ag salts or complexes can be use as co-catalysts. Examples are Ag(I)triflate or AgNO₃.

The Au catalyst is used in catalytic, i.e. substoichiometric amounts,e.g. in an amount of from 0.001 to 0.5 mol per mol of diol, inparticular 0.005 to 0.2 mol per mol of diol, specifically 0.005 to 0.1per mol of diol, more specifically 0.01 to 0.05 mol per mol of diol.

Also the Ag co-catalyst is used in catalytic, i.e. substoichiometricamounts, e.g. in an amount of from 0.001 to 0.5 mol per mol of diol, inparticular 0.005 to 0.2 mol per mol of diol, specifically 0.005 to 0.1per mol of diol, more specifically 0.01 to 0.05 mol per mol of diol.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 20° C. to 50° C.

The reaction can be carried out, e.g., by mixing all reagents, inclusivecatalyst or catalyst precursor and ligand(s), water and the cellulosederivative and reacting them at the desired temperature. Alternativelythe reagents can be added gradually, especially in the case of acontinuous or semicontinuous process.

If the catalyst ligand or any reactant is prone to oxidation by air, thereaction is preferably carried out in an inert atmosphere in order toavoid the presence of oxygen, e.g. under an argon or nitrogenatmosphere. Preferably, moreover, the solvent is used in degassed form.On a laboratory scale this is e.g. obtained by freezing, applying avacuum and unfreezing under an inert atmosphere or by bubbling avigorous stream of argon or nitrogen through the solvent or byultrasonification under an inert atmosphere. On an industrial scaleother methods known in the art can be applied.

Workup proceedings will be described below, as they are similar for mostreactions.

Cyclizations of Alkynenols

Alcohols containing an appropriately positioned alkenyl and alkynylgroup (C—C triple bond) can undergo transition metal-catalyzed ringclosure. For instance, an alkenyne carrying in α-position to the alkenegroup an OH group undergoes cyclization to the corresponding furane, asshown in the scheme below; an alkenyne carrying in β-position to thealkene group an OH group undergoes cyclization to the correspondingpyrane, etc.

R¹, R², R³ and R⁴ are independently of each other H, alkyl, cycloalkyl,aryl, heterocyclyl or heteroaryl.

The alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups R¹, R²,R³ and R⁴ can carry one or more substituents. Suitable substituents foralkyl, cycloalkyl, aryl or heteroaryl groups R¹, R², R³ and R⁴correspond to those listed above in context with substituents on thealkyl, cycloalkyl, aryl or heteroaryl groups R¹ and R² in the Suzukicoupling. Suitable substituents for heterocyclyl groups R¹, R², R³ andR⁴ correspond to those listed above in context with substituents on thecycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, aryl or heteroaryl groups R¹ and R² in the Suzukicoupling.

Suitable catalysts are for example Ru, Pd, Ag and Au catalysts, amongwhich Au catalysts generally give the best results.

Suitable Au catalysts are Au(III) salts and Au complexes. Examples forsuitable Au salts are AuCl₃, AuBr₃ or Au(triflate)₃. Suitable complexesare for example (Ph₃P)AuCl, [c-Hex₂(o-biphenyl)]PAuCl or[t-Bu₂(o-biphenyl)]PAuCl.

Ag salts or complexes can be use as co-catalysts. Examples are Ag(I)triflate or AgNO₃.

The Au catalyst is used in catalytic, i.e. substoichiometric amounts,e.g. in an amount of from 0.001 to 0.5 mol per mol of diol, inparticular 0.005 to 0.2 mol per mol of alkenynol, specifically 0.005 to0.1 per mol of alkenynol, more specifically 0.01 to 0.05 mol per mol ofalkenynol.

Also the Ag co-catalyst is used in catalytic, i.e. substoichiometricamounts, e.g. in an amount of from 0.001 to 0.5 mol per mol ofalkenynol, in particular 0.005 to 0.2 mol per mol of alkenynol,specifically 0.005 to 0.1 per mol of alkenynol, more specifically 0.01to 0.05 mol per mol of alkenynol.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 20° C. to 50° C.

The reaction can be carried out, e.g., by mixing all reagents, inclusivecatalyst or catalyst precursor and ligand(s), water and the cellulosederivative and reacting them at the desired temperature. Alternativelythe reagents can be added gradually, especially in the case of acontinuous or semicontinuous process.

If the catalyst ligand or any reactant is prone to oxidation by air, thereaction is preferably carried out in an inert atmosphere in order toavoid the presence of oxygen, e.g. under an argon or nitrogenatmosphere. Preferably, moreover, the solvent is used in degassed form.On a laboratory scale this is e.g. obtained by freezing, applying avacuum and unfreezing under an inert atmosphere or by bubbling avigorous stream of argon or nitrogen through the solvent or byultrasonification under an inert atmosphere. On an industrial scaleother methods known in the art can be applied.

Workup proceedings will be described below, as they are similar for mostreactions.

Cyclization of Alkynones

Carbonyl compounds, especially aldehydes or ketones, containing anappropriately positioned alkynyl group (C—C triple bond) can undergotransition metal-catalyzed ring closure. For instance, an alkynecarrying in β-position to the alkyne group a C(O) group undergoescyclization to the corresponding furane, as shown in the scheme below;an alkyne carrying in γ-position to the alkene group a C(O) groupundergoes cyclization to the corresponding pyrane, etc.

R¹, R² and R³ are independently of each other H, alkyl, cycloalkyl,aryl, heterocyclyl or heteroaryl.

The alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups R¹, R²and R³ can carry one or more substituents. Suitable substituents foralkyl, cycloalkyl, aryl or heteroaryl groups R¹, R² and R³ correspond tothose listed above in context with substituents on the alkyl,cycloalkyl, aryl or heteroaryl groups R¹ and R² in the Suzuki coupling.Suitable substituents for heterocyclyl groups R¹, R² and R³ correspondto those listed above in context with substituents on the cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, aryl or heteroaryl groups R¹ and R² in the Suzukicoupling.

Suitable catalysts are for example Ru, Pd, Ag and Au catalysts, amongwhich Au catalysts generally give the best results.

Suitable Au catalysts are Au(III) salts and Au complexes. Examples forsuitable Au salts are AuCl₃, AuBr₃ or Au(triflate)₃. Suitable complexesare for example (Ph₃P)AuCl, [c-Hex₂(o-biphenyl)]PAuCl or[t-Bu₂(o-biphenyl)]PAuCl.

Ag salts or complexes can be use as co-catalysts. Examples are Ag(I)triflate or AgNO₃.

The Au catalyst is used in catalytic, i.e. substoichiometric amounts,e.g. in an amount of from 0.001 to 0.5 mol per mol of alkynone, inparticular 0.005 to 0.2 mol per mol of alkynone, specifically 0.005 to0.1 per mol of alkynone, more specifically 0.01 to 0.05 mol per mol ofalkynone.

Also the Ag co-catalyst is used in catalytic, i.e. substoichiometricamounts, e.g. in an amount of from 0.001 to 0.5 mol per mol of alkynone,in particular 0.005 to 0.2 mol per mol of alkynone, specifically 0.005to 0.1 per mol of alkynone, more specifically 0.01 to 0.05 mol per molof alkynone.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 20° C. to 50° C.

The reaction can be carried out, e.g., by mixing all reagents, inclusivecatalyst or catalyst precursor and ligand(s), water and the cellulosederivative and reacting them at the desired temperature. Alternativelythe reagents can be added gradually, especially in the case of acontinuous or semicontinuous process.

If the catalyst ligand or any reactant is prone to oxidation by air, thereaction is preferably carried out in an inert atmosphere in order toavoid the presence of oxygen, e.g. under an argon or nitrogenatmosphere. Preferably, moreover, the solvent is used in degassed form.On a laboratory scale this is e.g. obtained by freezing, applying avacuum and unfreezing under an inert atmosphere or by bubbling avigorous stream of argon or nitrogen through the solvent or byultrasonification under an inert atmosphere. On an industrial scaleother methods known in the art can be applied.

Workup proceedings will be described below, as they are similar for mostreactions.

Cyclization of Allenones

Carbonyl compounds, especially aldehydes or ketones, containing anappropriately positioned allene group can undergo transitionmetal-catalyzed ring closure. For instance, an allene carrying inα-position to the allene group a C(O) group undergoes cyclization to thecorresponding furane, as shown in the scheme below; an allene carryingin β-position to the allene group a C(O) group undergoes cyclization tothe corresponding pyrane, etc.

R¹, R² and R³ are independently of each other H, alkyl, cycloalkyl,aryl, heterocyclyl or heteroaryl.

The alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups R¹, R²and R³ can carry one or more substituents. Suitable substituents foralkyl, cycloalkyl, aryl or heteroaryl groups R¹, R² and R³ correspond tothose listed above in context with substituents on the alkyl,cycloalkyl, aryl or heteroaryl groups R¹ and R² in the Suzuki coupling.Suitable substituents for heterocyclyl groups R¹, R² and R³ correspondto those listed above in context with substituents on the cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, aryl or heteroaryl groups R¹ and R² in the Suzukicoupling.

Suitable catalysts are for example Ru, Pd, Ag and Au catalysts, amongwhich Au catalysts generally give the best results.

Suitable Au catalysts are Au(III) salts and Au complexes. Examples forsuitable Au salts are AuCl₃, AuBr₃ or Au(triflate)₃. Suitable complexesare for example (Ph₃P)AuCl, [c-Hex₂(o-biphenyl)]PAuCl or[t-Bu₂(o-biphenyl)]PAuCl.

Ag salts or complexes can be use as co-catalysts. Examples are Ag(I)triflate or AgNO₃.

The Au catalyst is used in catalytic, i.e. substoichiometric amounts,e.g. in an amount of from 0.001 to 0.5 mol per mol of allenone, inparticular 0.005 to 0.2 mol per mol of allenone, specifically 0.005 to0.1 per mol of allenone, more specifically 0.01 to 0.05 mol per mol ofallenone.

Also the Ag co-catalyst is used in catalytic, i.e. substoichiometricamounts, e.g. in an amount of from 0.001 to 0.5 mol per mol of allenone,in particular 0.005 to 0.2 mol per mol of allenone, specifically 0.005to 0.1 per mol of allenone, more specifically 0.01 to 0.05 mol per molof allenone.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 20° C. to 50° C.

The reaction can be carried out, e.g., by mixing all reagents, inclusivecatalyst or catalyst precursor and ligand(s), water and the cellulosederivative and reacting them at the desired temperature. Alternativelythe reagents can be added gradually, especially in the case of acontinuous or semicontinuous process.

If the catalyst ligand or any reactant is prone to oxidation by air, thereaction is preferably carried out in an inert atmosphere in order toavoid the presence of oxygen, e.g. under an argon or nitrogenatmosphere. Preferably, moreover, the solvent is used in degassed form.On a laboratory scale this is e.g. obtained by freezing, applying avacuum and unfreezing under an inert atmosphere or by bubbling avigorous stream of argon or nitrogen through the solvent or byultrasonification under an inert atmosphere. On an industrial scaleother methods known in the art can be applied.

Workup proceedings will be described below, as they are similar for mostreactions.

Formation of Alcohols or Ethers Via C—O Coupling

The copper-mediated synthesis of biaryl ethers by reaction of anaromatic halide or pseudohalide and a hydroxyaromatic compound to abiaryl ether is known as the Ullmann biaryl ether synthesis orcondensation. In the method of the present invention, the use of Cu ishowever not mandatory; any transition metal catalyst can be used. Mostlya Pd catalyst is used.

Moreover, the oxygen source is not limited to an aromatic hydroxylcompound, but can be any compound with a nucleophilic OH group. Thus, anaromatic or heteroaromatic compound R¹—X, where R¹ is an aryl orheteroaryl group and X is a halogen atom or a pseudohalide group, suchas SCN, and is in particular Cl, Br, I or SCN, is reacted with a metalhydroxide, such as alkali metal hydroxide, e.g. LiOH, NaOH or KOH, or anearth alkaine metal hydroxide, such as Mg(OH)₂ or Ca(OH)₂, to yield analcohol R¹—OH; or with a hydroxyl compound R²—OH, where R² is alkyl,alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, heterocyclyl, aryl or heteroaryl, to yield an etherR¹—O—R².

In a particular embodiment the aryl group R¹ is mono-, bi- or tricyclicand is specifically selected from the group consisting of phenyl andnaphthyl; and the heteroaryl group R¹ is in particular mono-, bi- ortricyclic and is specifically selected from the group consisting of 5-or 6-membered heteroaromatic monocyclic rings and 9- or 10-memberedheteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members. Mono-or bicyclic aryl or heteroaryl groups R¹ are for example phenyl,naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl,isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl,[1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls,pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl,isoquinolinyl, quinazalinyl and the like. More particularly, they arefor example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl,1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl,1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl,1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl,1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl,4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl,1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl,1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl,indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromaticbicyclic rings shown below in the “general definitions”.

The aryl and heteroaryl groups R¹ can carry one or more substituents,e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2substituents. Suitable substituents are listed above in context witharyl and heteroaryl groups R¹ and R² in the Suzuki reaction.

In these substituents, however, all functional groups, especiallyhalogen atoms, pseudohalogen groups and sulfonyloxy groups, have to beless reactive towards the hydroxide or hydroxyl compound than thehalogen atom or pseudohalide group on the desired reaction site of theR¹—X compound.

In a particular embodiment, the substituents are selected from the groupconsisting of halogen (provided this is less reactive than X in the C—Ocoupling reaction), cyano (provided this is less reactive than X in theC—O coupling reaction), nitro, C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₂-C₆-alkenyl, C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl,C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkythio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, Oand S as ring members and a 9- or 10-membered heteroaromatic bicyclicring containing 1, 2, 3 or 4 heteroatoms selected from the groupconsisting of N, O and S as ring members, where phenyl and theheteroaromatic rings may carry one or more substituents selected fromthe group consisting of fluorine, cyano, nitro, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl, C₂-C₆-alkynyl,C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, formyl, C₁-C₄-alkylcarbonyl,C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl andC₁-C₄-haloalkoxycarbonyl. Specifically, the substituents are selectedfrom the group consisting of C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl andC₃-C₈-halocycloalkyl-C₁-C₆-alkyl.

Very specifically, R¹ is selected from the group consisting of phenyland naphthyl, where phenyl and naphthyl may carry 1, 2 or 3,specifically 1 or 2 substituents as defined above.

The alkyl, alkenyl, alkapolyenyl, alkynyl, mixed alkenyl/alkynyl,alkapolyynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl orheteroaryl groups R² can carry one or more substituents. Suitablesubstituents correspond to those listed above in context withsubstituents on the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl,mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling. Suitable substituents for heterocyclylgroups R² correspond to those listed above in context with substituentson the cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling.

Suitable Pd catalysts (inclusive ligands) are those mentioned above incontext with the Suzuki coupling.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 20° C. to 50° C.

The halogenide or pseudohalogenide and the OH compound (metal hydroxideor hydroxyl compound) can be used in a molar ratio of from 10:1 to 1:10,e.g. from 7:1 to 1:7 or from 5:1 to 1:5.

The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g.in an amount of from 0.001 to 0.1 mol per mol of that reactant which isnot used in excess, in particular 0.005 to 0.07 mol per mol of thereactant not used in excess. If the reactants are used in equimolarratio, the above amounts of catalyst apply of course to either of thereactants.

The reaction can be carried out by standard proceedings for suchreactions, e.g. by mixing all reagents, inclusive catalyst or catalystprecursor and ligand(s), water and the cellulose derivative and reactingthem at the desired temperature. Alternatively the reagents can be addedgradually, especially in the case of a continuous or semicontinuousprocess.

If the catalyst ligand or any reactant is prone to oxidation by air(such as is the case, for example, for triphenylphosphine,tri(tert-butyl)phosphine, X-Phos,6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphineand several others), the reaction is preferably carried out in an inertatmosphere in order to avoid the presence of oxygen, e.g. under an argonor nitrogen atmosphere. Preferably, moreover, the solvent is used indegassed form. On a laboratory scale this is e.g. obtained by freezing,applying a vacuum and unfreezing under an inert atmosphere or bybubbling a vigorous stream of argon or nitrogen through the solvent orby ultrasonification under an inert atmosphere. On an industrial scaleother methods known in the art can be applied.

Workup proceedings will be described below, as they are similar for mostreactions.

d) C—B Coupling Reactions

In a particular embodiment, the transition metal catalyzed reaction is aC—B coupling reaction. Transition metal catalyzed C—B coupling reactionsare well known. Examples are the Miyaura boration or borylation.

Miyaura Borylation

The Pd-catalyzed C—B coupling reaction of alkenyl, aryl or heteroarylhalides or sulfonates with tetraalkoxydiboron compounds is calledMiyaura borylation. The resulting aryl boronic esters are valuablesubstrates for Suzuki coupling reactions, Ullmann biaryl ether synthesesand the above described 1,4 additions of organoborane compounds toα,β-olefinically unsaturated carbonyl compounds, such as theRh-catalyzed 1,4-addition reactions.

Preferably, a halogenide or sulfonate R²—(Z)_(n), where R² is analkenyl, aryl or heteroaryl group, Z is a halogenide or sulfonate group(the sulfonate being in particular a fluorinated alkylsulfonate ortosylate, specifically triflate or nonaflate) and n is 1, 2, 3 or 4, isreacted with a tetraalkoxydiboron (R¹O)₂B—B(OR¹)₂, where R¹ is alkyl ortwo R¹ bound on oxygen atoms bound in turn to the same B atom formtogether —C(CH₃)₃—C(CH₃)₂— (so that B(OR¹)₂ is the pinacolon ester ofboronic acid), in the presence of a transition metal catalyst, inparticular of a Pd catalyst, and in general also of a base.

The reaction of the tetraalkoxydiboron (R¹O)₂B—B(OR¹)₂ with R²—(Z)_(n)yields a compound (B(OR¹)₂)_(n)—R². The alkenyl, aryl or heteroarylhalide or sulfonate can contain more than one halide or sulfonate group(when n is 2, 3 or 4), so that multiply coupled compounds can form,especially if the tetraalkoxydiboron compound is used in excess. Forinstance, a difunctional compound R²—(Z)₂ can yield a twofold coupledcompound tetraalkoxydiboron (R¹O)₂B—R²—B(OR¹)₂.

Due to the tolerance of the Miyaura borylation to a wide variety offunctional groups, the alkenyl, aryl or heteroaryl groups R² can carryone or more substituents. Suitable substituents correspond to thoselisted above in context with substituents on the alkenyl, aryl orheteroaryl groups R¹ and R² in the Suzuki coupling.

In these substituents, however, all functional groups, especiallyhalogen atoms and sulfonyloxy groups, have to be less reactive towardsthe diboron compound than the halogen atom or sulfonate group on thedesired reaction site of the R²—(Z)_(n) compound.

Suitable Pd catalysts (inclusive ligands) are those mentioned above incontext with the Suzuki coupling.

Suitable bases can be inorganic or organic. Examples for suitable arethose listed in context with the Suzuki reaction.

Specifically, the present method relates to a Miyaura borylation inwhich an aromatic or heteroaromatic halogenide R²—(Z)_(n), where R² is amono-, bi- or polycyclic aryl or heteroaryl group, Z is a halogen atom,especially Cl, Br or I, more specifically Br or I, and n is 1, isreacted with a tetraalkoxydiboron, specifically withbis(pinacolato)diboron, in the presence of a Pd catalyst, specificallyof bis(tritert-butyl-butylphosphine) palladium(0), and in the presenceof a base, specifically of an acetate, specifically sodium or potassiumacetate.

In a particular embodiment the aryl group R² is mono-, bi- or tricyclicand is specifically selected from the group consisting of phenyl andnaphthyl; and the heteroaryl group R² is in particular mono-, bi- ortricyclic and is specifically selected from the group consisting of 5-or 6-membered heteroaromatic monocyclic rings and 9- or 10-memberedheteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members. Mono-or bicyclic aryl or heteroaryl groups R² are for example phenyl,naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl,isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl,[1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls,pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl,isoquinolinyl, quinazalinyl and the like. More particularly, they arefor example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl,1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl,1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl,1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl,1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl,4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl,1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl,1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl,indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromaticbicyclic rings shown below in the “general definitions”.

The aryl and heteroaryl groups R² can carry one or more substituents,e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2substituents. Suitable substituents are listed above in context witharyl and heteroaryl groups R¹ and R² in the Suzuki reaction. In aparticular embodiment, the substituents on the aryl and heteroarylgroups R² are selected from the group consisting of fluorine, cyano,nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members and a 9- or 10-memberedheteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members, wherephenyl and the heteroaromatic rings may carry one or more substituentsselected from the group consisting of fluorine, cyano, nitro, OH, SH,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino. Specifically, the substituents on the aryl andheteroaryl groups R² are selected from the group consisting of fluorine,cyano, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 20° C. to 50° C.

The halogenide or sulfonate and the tetraalkoxydiboron can be used in amolar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to1:5. In case of di- or polyfunctional halides or sulfonates, the molarratio relates of course to the number of halide or sulfonate groups inthe molecule. If n is 1, R²—(Z)_(n) and the tetraalkoxydiboron arepreferably used in a molar ratio of from 2:1 to 1:2, more preferablyfrom 1.5:1 to 1:1.5 and specifically from 1:1 to 1:1.5. If n is 2,R²—(Z)_(n) and R¹—BY₂ are preferably used in a molar ratio of from 1:1to 1:4, more preferably from 1:1.5 to 1:3 and specifically in a molarratio of from 1:2 to 1:3.

The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g.in an amount of from 0.001 to 0.1 mol per mol of that reactant which isnot used in excess, in particular 0.005 to 0.07 mol per mol of thereactant not used in excess, specifically 0.01 to 0.07 mol per mol ofthe reactant not used in excess. If the reactants are used in equimolarratio, the above amounts of catalyst apply of course to either of thereactants.

The base is generally used in excess, i.e. in overstoichiometric amountswith respect to that reactant not used in excess, e.g. in an amount offrom 1.5 to 5 mol per mol of the reactant not used in excess, inparticular 1.5 to 4 mol per mol of the reactant not used in excess,specifically 1.5 to 3 mol per mol of the reactant not used in excess. Ifthe reactants are used in equimolar ratio, the above amounts of baseapply of course to either of the reactants.

The reaction can be carried out by standard proceedings for Miyauraborylations, e.g. by mixing all reagents, inclusive catalyst or catalystprecursor and ligand(s) and base, water and the cellulose derivative andreacting them at the desired temperature. Alternatively the reagents canbe added gradually, especially in the case of a continuous orsemicontinuous process.

If the catalyst ligand or any reactant is prone to oxidation by air(such as is the case, for example, for triphenylphosphine,tri(tert-butyl)phosphine, X-Phos,6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphineand several others), the reaction is preferably carried out in an inertatmosphere in order to avoid the presence of oxygen, e.g. under an argonor nitrogen atmosphere. Preferably, moreover, the solvent is used indegassed form. On a laboratory scale this is e.g. obtained by freezing,applying a vacuum and unfreezing under an inert atmosphere or bybubbling a vigorous stream of argon or nitrogen through the solvent orby ultrasonification under an inert atmosphere. On an industrial scaleother methods known in the art can be applied.

Workup proceedings will be described below, as they are similar for mostreactions.

e) C-Halogen Coupling

In this reaction a C—H bond is converted into a C-halogen bond byreaction with a halogenating agent in the presence of a transition metalcatalyst. In a specific embodiment an aromatic or heteroaromaticcompound R¹—H, where R¹ is aryl or heteroaryl, is reacted with ahalogenating agent in the presence of a transition metal catalyst toyield a compound R¹—X, where X is a halogen atom, especially Cl, Br orI, very specifically Cl or Br.

Suitable transition metal catalysts are those mentioned above. Inparticular, an Au or a Pd catalyst is used. Specifically an Au catalystis used.

Suitable Au catalysts are Au(I) salts and Au complexes.

Suitable Pd catalysts (inclusive ligands) are those mentioned above incontext with the Suzuki coupling.

Suitable halogenation reagents are for example the halogens, i.e. F₂,Cl₂, Br₂ or I₂, oxalyl chloride, oxalyl bromide, thionyl chloride,thionyl bromide, sulfuryl chloride, sulfuryl bromide, N-bromosuccinimide(NBS), N-chlorosuccinimide (NCS), dichlorodimethylhydantoin,dibromodimethylhydantoin, trichlorisocyanuric acid, chloramine-T, PCl₅,P(O)Cl₃, sodium hypochlorite, monochloroamine (NH₂Cl) and the like. In aspecific embodiment NBS or NCS is used.

In a particular embodiment aryl group R¹ is mono-, bi- or tricyclic andare specifically selected from the group consisting of phenyl andnaphthyl; and heteroaryl group R¹ is in particular mono-, bi- ortricyclic and are specifically selected from the group consisting of 5-or 6-membered heteroaromatic monocyclic rings and 9- or 10-memberedheteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members. Mono-or bicyclic aryl or heteroaryl groups R¹ are for example phenyl,naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl,isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl,[1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls,pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl,isoquinolinyl, quinazalinyl and the like. More particularly, they arefor example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl,1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl,1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl,1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl,1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl,4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl,1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl,1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl,indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromaticbicyclic rings shown below in the “general definitions”.

The aryl and heteroaryl groups R¹ can carry one or more substituents,e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2substituents. Suitable substituents are listed above in context witharyl and heteroaryl groups R¹ and R² in the Suzuki reaction. In aparticular embodiment, the substituents on the aryl and heteroarylgroups R¹ are selected from the group consisting of fluorine, cyano,nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members and a 9- or 10-memberedheteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members, wherephenyl and the heteroaromatic rings may carry one or more substituentsselected from the group consisting of fluorine, cyano, nitro, OH, SH,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino. Specifically, the substituents on the aryl andheteroaryl groups R¹ are selected from the group consisting of fluorine,cyano, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 20° C. to 50° C.

The (hetero)aromatic compound and the halogenating agent can be used ina molar ratio of from 10:1 to 1:10. More often, however, thehalogenating agent is used in at least equimolar amounts, especially ifa halogen is used as halogenating agent.

The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g.in an amount of from 0.001 to 0.1 mol per mol of that reactant which isnot used in excess, in particular 0.005 to 0.07 mol per mol of thereactant not used in excess. If the reactants are used in equimolarratio, the above amounts of catalyst apply of course to either of thereactants.

The reaction can be carried out by standard proceedings forhalogenations, e.g. by mixing all reagents, inclusive catalyst orcatalyst precursor and ligand(s), water and the cellulose derivative andreacting them at the desired temperature. Alternatively the reagents canbe added gradually, especially in the case of a continuous orsemicontinuous process. If the halogenating agent is gaseous, e.g.fluorine or chlorine, generally all reagents but the gaseous halogen aremixed and the halogen gas is then bubbled through the reaction mixture.If the reaction is carried out at temperatures above or below ambientconditions, the mixture can be brought to the desired temperature beforeor during the introduction of the halogen gas.

If the catalyst ligand or any reactant is prone to oxidation by air(such as is the case, for example, for triphenylphosphine,tri(tert-butyl)phosphine, X-Phos,6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphineand several others), the reaction is preferably carried out in an inertatmosphere in order to avoid the presence of oxygen, e.g. under an argonor nitrogen atmosphere. Preferably, moreover, the solvent is used indegassed form. On a laboratory scale this is e.g. obtained by freezing,applying a vacuum and unfreezing under an inert atmosphere or bybubbling a vigorous stream of argon or nitrogen through the solvent orby ultrasonification under an inert atmosphere. On an industrial scaleother methods known in the art can be applied.

Workup proceedings will be described below, as they are similar for mostreactions. If the halogenating agent is used in excess, this isgenerally neutralized before further workup.

C—C Coupling Reactions not Requiring Transition Metal Catalysis

In another particular embodiment of the invention, the organic reactionis a C—C coupling reaction not requiring transition metal catalysis.Such reactions are well known and often named reactions. Examples arevarious reactions of carbonyl compounds or nitrile compounds, e.g. withnucleophiles, e.g. with CH acidic compounds, like the Wittig reaction,the Baylis-Hillman reaction, the Aldol addition and condensation, theKnoevenagel condensation, the Michael addition, the Mannich reaction,the Perkin reaction, the Erlenmeyer reaction, the Darzens reaction, theacyloin condensation, Friedel Crafts alkylation and acylation, Grignardreaction etc; further pericyclic reactions like the Diels-Alderreaction, cyclopropanation reactions (without transition metal catalysisin this context) etc. In particular, the C—C coupling reaction notrequiring transition metal catalysis is a Wittig reaction, a Diels-Alderreaction or a Baylis-Hillman reaction.

Wittig Reaction

In a particular embodiment, the C—C coupling reaction not requiringtransition metal catalysis is a Wittig reaction. The formation of C—Cdouble bonds from carbonyl compounds and phosphoranes (phosphorousylides) is known as the Wittig reaction. In the below scheme both thephosphorous ylide and ylene mesomeric forms are shown:

The phosphorous ylide is generally prepared from a triaryl or trialkylphosphine, mostly triphenyl phosphine, and an alkyl halide followed bydeprotonation with a suitable base, such as BuLi, sodium hydride orsodium methanolate.

R¹ is in general an aryl group, especially phenyl. R² and R³ aregenerally independently of each other hydrogen, alkyl, alkenyl,alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, heterocyclyl, aryl, heteroaryl, CN, C(O)R¹³, C(S)R¹³ orS(O)₂R¹¹. The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl andheteroaryl groups R¹, R² and R³ can carry one or more substituents.Suitable substituents for alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl andheteroaryl correspond to those listed above in context with substituentson the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling. Suitable substituents for heterocyclylgroups correspond to those listed above in context with substituents onthe cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling. R¹¹ and R¹³ are as defined above incontext with the Suzuki coupling.

R⁴ and R⁵ are independently of each other hydrogen, alkyl, alkenyl,alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, heterocyclyl, aryl or heteroaryl. Alkyl, alkenyl,alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, heterocyclyl, aryl, heteroaryl can carry one or moresubstituents. Suitable substituents for alkyl, alkenyl, alkapolyenyl,alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl,heterocyclyl, aryl and heteroaryl correspond to those listed above incontext with substituents on the alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolyynyl, mixed alkenyl/alkynyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling. Suitable substituents for heterocyclylgroups correspond to those listed above in context with substituents onthe cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling.

Important variants of the Wittig reaction are

1) Horner-Wittig or Wittig-Horner reaction, in which the phosphorousylides contain phosphine oxides in place of triarylphosphines ortrialkylphosphines;

2) the Horner-Wadsworth-Emmons reaction, in whichalkylphosphonicdiethylesters are the phosphorus reagents:

3) the Schlosser modification in which two equivalents of a Li-halidesalt are present in the reaction mixture.

In the terms of the present invention the “Wittig reaction” encompassesall these variants.

In the proper Wittig reaction, the ylides can be stabilized,semi-stabilized or nonstabilized. In the stabilized ylides thealkylhalide component has at least one strong electron-withdrawing group(—COOR, C(O)R, S(O)₂R, CN etc.) which stabilizes the formal negativecharge on the C atom. In the semi-stabilized ylides the alkylhalidecomponent has at least one alkenyl or aryl substituent (i.e. at leastone of R² and R³ is alkenyl or aryl). In the nonstabilized ylides thealkylhalide component has only alkyl substituent(s).

In particular, the C—C coupling reaction not requiring transition metalcatalysis is a Wittig reaction in the proper sense. Preferably the ylideused is a stabilized ylide. In particular, one of R² and R³ is a CN,C(O)R¹³, C(S)R¹³ or S(O)₂R¹¹ group and especially a C(O)OR²⁰ group,where R¹¹, R¹³ and R²⁰ are as defined above in context with the Suzukicoupling. In particular, one of R² and R³ is C₁-C₄-alkoxycarbonyl. Theother radical is in particular hydrogen or C₁-C₄-alkyl.

In particular, one of R⁴ and R⁵ is hydrogen or C₁-C₄-alkyl and the otheris alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl orheteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, heteroaryl can carry one or more substituents. Specifically, oneof R⁴ and R⁵ is hydrogen or C₁-C₄-alkyl and the other is a mono-, bi- orpolycyclic aryl or heteroaryl group which may carry one or moresubstituents.

In a particular embodiment the aryl group R⁴ or R⁵ is mono-, bi- ortricyclic and is specifically selected from the group consisting ofphenyl and naphthyl; and the heteroaryl group R⁴ or R⁵ is in particularmono-, bi- or tricyclic and is specifically selected from the groupconsisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4heteroatoms selected from the group consisting of N, O and S as ringmembers. Mono- or bicyclic aryl or heteroaryl groups R⁴ or R⁵ are forexample phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl,[1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls,the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl,pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl,benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. Moreparticularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl,3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl,1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl,1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl,1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl,1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl,1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl,4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl,3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl,1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl,1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl,benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl,quinazalinyl and other heteroaromatic bicyclic rings shown below in the“general definitions”.

The aryl and heteroaryl groups R⁴ or R⁵ can carry one or moresubstituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1or 2 substituents. Suitable substituents are listed above in contextwith aryl and heteroaryl groups R¹ and R² in the Suzuki reaction. In aparticular embodiment, the substituents on the aryl and heteroarylgroups R⁴ or R⁵ are selected from the group consisting of halogen,cyano, nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members and a 9- or 10-memberedheteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members, wherephenyl and the heteroaromatic rings may carry one or more substituentsselected from the group consisting of fluorine, cyano, nitro, OH, SH,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonylamino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino. Specifically, the substituents on the aryl andheteroaryl groups R⁴ or R⁵ are selected from the group consisting ofhalogen, cyano, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, amino, C₁-C₄-alkylaminoand di-(C₁-C₄-alkyl)amino.

The carbonyl compound and the phosphorous ylide can be used in a molarratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5,preferably from 3:1 to 1:3 and in particular from 2:1 to 1:2, e.g. 1.5:1to 1:1.5.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 25° C. to 55° C. andvery specifically from 40° C. to 50° C.

The reaction can be carried out by standard proceedings for Wittigreactions, e.g. by mixing all reagents, water and the cellulosederivative and reacting them at the desired temperature. Alternativelythe reagents can be added gradually, especially in the case of acontinuous or semicontinuous process.

Workup proceedings will be described below, as they are similar for mostreactions.

Diels-Alder Reaction

In a particular embodiment, the C—C coupling reaction not requiringtransition metal catalysis is a Diels-Alder reaction. The [4π+2π]cyclization of a conjugated diene with a dienophile, e.g. an alkene, toa cyclohexene derivative is called Diels-Alder cycloaddition orDiels-Alder reaction.

Besides alkenes (as shown in the above reaction scheme), alkynes,benzynes or allenes are also good dienophiles. The diene is usuallyelectron rich and the dienophile is electron poor (this is called“normal electron-demand Diels-Alder reaction”). When the diene iselectron poor and the dienophile electron rich, this is called “inverseelectron-demand Diels-Alder reaction”. If the ring formed contains,apart from carbon ring atoms, one or more heteroatoms as ring member(s),this variant is called “hetero-Diels-Alder reaction”. Diels Alderreactions tolerate a wide variety of functional groups. Thus, R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are independently hydrogen, alkyl,alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, heterocyclyl, aryl or heteroaryl, or are one of thesubstituents listed in context with the Suzuki as suitable radicals onalkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl or mixedalkenyl/alkynyl groups (however except for oxo (═O), ═S and ═NR^(12a)).More precisely, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰,independently of each other, are hydrogen, alkyl, alkenyl, alkapolyenyl,alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl,heterocyclyl, aryl, or heteroaryl, halogen, cyano, nitro, azido, —SCN,—SF₅, OR¹¹, S(O)_(m)R¹¹, NR^(12a)R^(12b), C(═O)R¹³, C(═S)R¹³,C(═NR^(12a))R¹³ or —Si(R¹⁴)₃; where R¹¹, R^(12a), R^(12b), R¹³, R¹⁴ andR¹⁵ are independently as defined above in context with the Suzukireaction.

The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl,heteroaryl groups can in turn be substituted by one or moresubstituents. Suitable substituents for alkyl, alkenyl, alkapolyenyl,alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl andheteroaryl correspond to those listed above in context with substituentson the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling. Suitable substituents for heterocyclylgroups correspond to those listed above in context with substituents onthe cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling. Alternatively, R² and R³ and/or R³ and R⁴and/or R⁴ and R⁵ and/or R¹ and R⁶ and/or R⁷ and R⁹ can form a mono-, bi-or polycyclic carbocyclic or heterocyclic ring. This ring(s) may in turnbe substituted by one or more substituents. Suitable substituentscorrespond to those listed above in context with substituents on thearyl or heteroaryl groups R¹ and R² in the Suzuki coupling.

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are suitably chosen in such away that the diene is electron rich and the dienophile is electron pooror inversely the diene is electron poor and the dienophile is electronrich. Groups which enhance the electron density on the double bond arefor example alkyl groups, cycloalkyl groups, electron-rich heterocyclicrings, ether groups, amino groups, (di)alkyl amino groups. The alkyl,cycloalkyl or heterocyclic groups as well as the carbon atoms in theether or (di)alkyl amino groups may be substituted as described above,as the electronic influence of optional substituents decreasesdrastically with the distance to the double bond of the diene ordienophile. Electron-withdrawing groups are for example carbonyl groups(be it in the form of formyl, keto, carbamoyl, carboxyl or estergroups), sulfonyl groups, CN, the nitro group or halogen atoms. Carbonand nitrogen atoms in these groups (i.e. in keto, amido, ester orsulfonyl groups) may be substituted as described above, as theelectronic influence of optional substituents decreases drastically withthe distance to the double bond of the diene or dienophile.

In a particular embodiment of the present invention, an electron-richdiene and an electron-poor alkene are reacted. Specifically, R¹, R³, R⁴,R⁶, R⁷ and R⁹ are H, R⁷ and R⁹ are either both alkyl or one or R⁷ and R⁹is H and the other is alkyl, where alkyl can carry a substituent, wheresuitable substituents correspond to those listed above in context withsubstituents on the alkyl groups R¹ and R² in the Suzuki coupling, andis specifically a OR¹¹ group; and R⁸ and R¹⁰ are either both C(O)R¹³ orone of R⁸ and R¹⁰ is H and the other is C(O)R¹³, or R⁸ and R¹⁰ formtogether a bridging group —C(O)-A-C(O)—, where A is an alkylene bridgeor O or NR^(12a), where R¹¹, R^(12a) and R¹³ areas defined above incontext with the Suzuki coupling. Very specifically, R⁸ and R¹⁰ formtogether a bridging group —C(O)—N(R^(12a))—C(O)—, where R^(12a) is asdefined in context with the Suzuki coupling, and is specificallyC₁-C₆-alkyl. R¹¹ is very specifically a C₁-C₆-alkylcarbonyl group.

The diene and the dienophile can be used in a molar ratio of from 10:1to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5, preferably from 3:1 to1:3 and in particular from 2:1 to 1:2, e.g. 1.5:1 to 1:1.5.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 25° C. to 55° C. andvery specifically from 40° C. to 50° C.

The reaction can be carried out by standard proceedings for Diels-Alderreactions, e.g. by mixing all reagents, water and the cellulosederivative and reacting them at the desired temperature. Alternativelythe reagents can be added gradually, especially in the case of acontinuous or semicontinuous process.

Workup proceedings will be described below, as they are similar for mostreactions.

Baylis-Hillman Reaction

In a particular embodiment, the C—C coupling reaction not requiringtransition metal catalysis is a Baylis-Hillman reaction. Classically, inthis reaction type, a C—C single bond between the α-position ofconjugated carbonyl compounds, e.g. esters or amides, and carbonelectrophiles, e.g. aldehydes or activated ketones, in the presence of asuitable nucleophilic catalyst is formed:

R¹, R² and R³ are independently H, alkyl, alkenyl, alkapolyenyl,alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl,heterocyclyl, aryl or heteroaryl, or R¹ and R² form together with thecarbon atom they are bound to a carbocyclic or heterocyclic ring; X isOR or N(R)₂, where R is for example H, alkyl, cycloalkyl, heterocyclyl,aryl or heteroaryl, and Y is O or N substituted with anelectron-withdrawing group, such as an arylsulfonyl or an alkoxycarbonylgroup. The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl,heteroaryl groups, as well as the carbocyclic or heterocyclic ringformed by R¹ and R² together with the carbon atom they are bound to, canbe substituted by one or more substituents. Suitable substituents foralkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroarylcorrespond to those listed above in context with substituents on thealkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling. Suitable substituents for heterocyclylgroups and for the carbocyclic or heterocyclic ring formed by R¹ and R²together with the carbon atom they are bound to correspond to thoselisted above in context with substituents on the cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, aryl or heteroaryl groups R¹ and R² in the Suzukicoupling.

In these substituents, however, all functional groups have to be lessreactive than the desired reaction sites for the desired reaction.

In terms of the present invention, the Baylis-Hillman reaction alsoencompasses also the reaction of a conjugated nitrile compound with acarbon electrophile, e.g. an aldehydes or an activated ketone, in thepresence of a suitable nucleophilic catalyst:

R¹, R², R³ and Y are as defined above.

Nucleophilic catalysts are tertiary amines, e.g. trimethylamine,triethylamine, tripropylamine, diisopropylethylamine, tributylamine,morpholine, DABCO, DBU, DBN or quinuclidine; and tertiary phosphines,e.g. trialkylphosphines, like trimethyl, triethyl-, tripropyl- ortributylphosphine.

In some cases it is advantageous to carry out the reaction in thepresence of metal-derived Lews acids, such as AlCl₃, FeCl₃, TiCl₄ andthe like.

In a particular embodiment of the present invention, a conjugatednitrile compound, in which in the above scheme R³ is H, alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl and is specifically H, isreacted with an aldehyde, i.e. in the above scheme Y is O, R² is H and Ris H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl and isspecifically aryl, where alkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl groups can be substituted by one or more substituents.Suitable substituents for alkyl, cycloalkyl, aryl and heteroarylcorrespond to those listed above in context with substituents on thealkyl, cycloalkyl, aryl or heteroaryl groups R¹ and R² in the Suzukicoupling. Suitable substituents for heterocyclyl groups correspond tothose listed above in context with substituents on the cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, aryl or heteroaryl groups R¹ and R² in the Suzukicoupling.

In these substituents, however, all functional groups have to be lessreactive than the desired reaction sites for the desired reaction.

In a particular embodiment the aryl group R¹ is mono-, bi- or tricyclicand is specifically selected from the group consisting of phenyl andnaphthyl.

The aryl group R¹ can carry one or more substituents, e.g. 1, 2, 3 or 4,in particular 1, 2 or 3, specifically 1 or 2 substituents. Suitablesubstituents are listed above in context with aryl groups R¹ and R² inthe Suzuki reaction. In a particular embodiment, the substituents on thearyl group R¹ are selected from the group consisting of halogen, cyano,nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, C₁-C₄-alkylcarbonyl,C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl,amino, C₁-C₄-alkylamino, di-(C₁-C₄-alkyl)amino, phenyl, a 5- or6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4heteroatoms selected from the group consisting of N, O and S as ringmembers and a 9- or 10-membered heteroaromatic bicyclic ring containing1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O andS as ring members, where phenyl and the heteroaromatic rings may carryone or more substituents selected from the group consisting of fluorine,cyano, nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino. Specifically, the substituents on the aryl groupR¹ are selected from the group consisting of halogen, cyano,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl,C₃-C₈-cycloalkyl-C₁-C₆-alkyl, C₃-C₈-halocycloalkyl-C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, formyl, C₁-C₄-alkylcarbonyl,C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl,amino, C₁-C₄-alkylamino and di-(C₁-C₄-alkyl)amino.

The nucleophilic catalyst is in particular a tertiary amine, moreparticularly a cyclic amine, such as DABCO, DBU, DBN or quinuclidine,and is specifically DABCO.

The conjugated carbonyl or nitrile compound and the carbon electrophilecan be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7or from 5:1 to 1:5. Specifically, the carbon electrophile is used inexcess, e.g. in a 10-fold or 7-fold or 5-fold or 2-fold excess.

The nucleophilic catalyst is generally used in catalytic amounts, i.e.in substoichiometric amounts with respect to that reactant not used inexcess, e.g. in an amount of from 0.001 to 0.9 mol per mol of thatreactant which is not used in excess, in particular 0.01 to 0.7 mol permol of the reactant not used in excess, specifically 0.05 to 0.5 mol permol of the reactant not used in excess. If the reactants are used inequimolar ratio, the above amounts of catalyst apply of course to eitherof the reactants.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 20° C. to 50° C. andvery specifically from 20° C. to 30° C.

The reaction can be carried out by standard proceedings forBaylis-Hillman reactions, e.g. by mixing all reagents, water and thecellulose derivative and reacting them at the desired temperature.Alternatively the reagents can be added gradually, especially in thecase of a continuous or semicontinuous process.

Workup proceedings will be described below, as they are similar for mostreactions.

Carboxamide or Sulfonamide Bond Formation not Requiring Transition MetalCatalysis

In another particular embodiment of the invention, the organic reactionis a carboxamide or sulfonamide bond formation (not requiring transitionmetal catalysis).

Carboxamide Bond Formation

For the synthesis of carboxamides, generally a carboxylic acid or aderivative of a carboxylic acid capable of amide formation, for instancean acid halide, acid anhydride or ester, is reacted with a primary orsecondary amine.

R¹, R² and R³ are independently H, alkyl, alkenyl, alkapolyenyl,alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl,heterocyclyl, aryl or heteroaryl, or R² and R³ form together with thenitrogen atom they are bound to a mono-, bi- or polycyclic heterocyclicring; X is OH, OR⁴, O—C(O)—R^(1′) or a halogen atom, where R⁴ is alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl andR^(1′) is independently defined as R¹. Alternatively, X is anothercommon leaving group, for example thiophenyl or imidazolyl.

The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl,heteroaryl groups, as well as the the mono- bi- or polycyclicheterocyclic ring formed by R² and R³ together with the nitrogen atomthey are bound to, can be substituted by one or more substituents.Suitable substituents for alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl andheteroaryl correspond to those listed above in context with substituentson the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling. Suitable substituents for heterocyclylgroups and for the mono- bi- or polycyclic heterocyclic ring formed byR² and R³ together with the nitrogen atom they are bound to correspondto those listed above in context with substituents on the cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, aryl or heteroaryl groups R¹ and R² in the Suzukicoupling. If however these groups carry substituents which can competein the reaction, e.g. further amino groups, it is expedient to protectthese groups before the amidation reaction. For example, amino groupscan be protected by standard N-protective groups, such as boc, benzyl,F-moc etc. Suitable protective groups are for example described in T.Greene and P. Wuts, Protective Groups in Organic Synthesis (3^(rd) ed.),John Wiley & Sons, NY (1999). Alike, when these groups carry a COYsubstituent, where Y is as defined as X, Y has to be converted into agroup which is less reactive than X versus the amine. For instance, if Xis OH, Y has to be converted into an alkoxy group, such as methoxy orethoxy.

Amidation can be carried out by reacting the carboxylic acid (X=OH) withthe amine under heating and removal of reaction water, but is preferablycarried out by activation of the carboxylic acid with, e.g.oxalylchloride [(COCl)₂] or thionylchloride (SOCl₂) to the respectiveacid chloride (X=Cl), followed by reaction with amine.

Alternatively, amidation is carried out with the carboxylic acid in thepresence of a coupling reagent. Suitable coupling reagent (activators)are well known and are for instance selected from the group consistingof carbodiimides, such as EDCI(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; also abbreviated asEDC), DCC (dicyclohexylcarbodiimide) and DIC (diisopropylcarbodiimide),benzotriazole derivatives, such as HOBt (1-hydroxybenzotriazole), HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate), HBTU((O-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate)and HCTU (1H-benzotriazolium-1-[bis(dimethylamino)methylene]-5-chlorotetrafluoroborate), phosphonium-derived activators, such as BOP((benzotriazol-1-yloxy)-tris(dimethylamino)phosphoniumhexafluorophosphate), Py-BOP((benzotriazol-1-yloxy)-tripyrrolidinphosphonium hexafluorophosphate)and Py-BrOP (bromotripyrrolidinphosphonium hexafluorophosphate), andothers, such as COMU((1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium-hexafluorophosphat).The above activators can also be used in combination with each other.Generally, the activator is used in at least equimolar amounts, withrespect to that reactant not used in excess. The benzotriazole andphosphonium coupling reagents are generally used in a basic medium.

Suitable esters R¹—COOR⁴ derive expediently from C₁-C₄-alkanols R⁴OH inwhich R⁴ is C₁-C₄-alkyl, such as methanol, ethanol, propanol,isopropanol, n-butanol, butan-2-ol, isobutanol and tert-butanol,preference being given to the methyl and ethyl esters (R⁴=methyl orethyl). Suitable esters may also derive from C₂-C₆-polyols such asglycol, glycerol, trimethylolpropane, erythritol, pentaerythritol andsorbitol, preference being given to the glyceryl ester. When polyolesters are used, it is possible to use mixed esters, i.e. esters withdifferent R⁴ radicals.

Alternatively, the ester R¹—COOR⁴ is a so-called active ester, which isobtained in a formal sense by the reaction of the acid R¹—COOH with anactive ester-forming alcohol, such as p-nitrophenol,N-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide or OPfp(pentafluorophenol).

The acid anhydride R¹—CO—O—OC—R^(1′) is either a symmetric anhydrideR¹—CO—O—OC—R¹ (R^(1′)═R¹) or an asymmetric anhydride in which—O—OC—R^(1′) is a group which can be displaced easily by the amineHN(R²)R³. Suitable acid derivatives with which the carboxylic acidR¹—COOH can form suitable mixed anhydrides are, for example, the estersof chloroformic acid, for example isopropyl chloroformate and isobutylchloroformate, or of chloroacetic acid.

If X is a halogen atom, the reaction is generally carried out in thepresence of a base. Suitable bases are those listed above in contextwith the Suzuki reaction.

In a particular embodiment of the present invention, a carboxylic acid(X=OH) is reacted with a primary or secondary amine in the presence ofone or two coupling reagents, specifically of EDCI, HOBt or COMU or acombination thereof.

In a particular embodiment, R¹ is alkyl or aryl, where the alkyl or arylgroup may be substituted as described above. Specifically, R¹ isC₁-C₁₀-alkyl which may carry a phenyl ring, which may in turn besubstituted as described above and in particular by one or more R¹⁵, ormay carry a group C(O)R¹³ or N(R^(12a))R^(12b), where R^(12a), R^(12b),R¹³ and R¹⁵ are as defined in context with the Suzuki reaction; or R¹ isphenyl which may be substituted as described above and in particular byone or more R¹⁵. Specifically R¹³ is C₁-C₄-alkyl. Specifically R^(12a)and R^(12b) are H, but one of them is replaced by a protective group,such as boc, benzyl or F-moc.

In a particular embodiment, R² is H and R³ is alky or aryl, where thealkyl or aryl group may be substituted as described above, or R² and R³form together with the nitrogen atom they are bound to a mono-, bi- orpolycyclic ring, such as piperidine-1-yl, 1-alkyl-piperazin-4-yl,morpholinyl, pyrrolidin-1-yl, pyrrolin-1-yl, pyrrol-1-yl, indolin-1-yl,indol-1-yl etc. Specifically, R³ is C₁-C₁₀-alkyl which may carry aphenyl ring, which may in turn be substituted as described above and inparticular by one or more R¹⁵, or is C(O)R¹³, or is N(R^(12a))R^(12b),where R^(12a), R^(12b), R¹³ and R¹⁵ are as defined in context with theSuzuki reaction. Specifically R¹³ is C₁-C₆-alkyl. Specifically R^(12a)and R^(12b) are both C₁-C₁₀-alkyl or are both H, where however one ofthe hydrogen atoms is replaced by a protective group, such as boc,benzyl or F-moc.

The acid (derivative) and the amine can be used in a molar ratio of from10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5. In particular,they are used in a molar ratio of from 3:1 to 1:3, more particularly 2:1to 1:2 and specifically from 1.5:1 to 1:1.5.

If the amidation is carried out in the presence of a coupling agent,this is generally used in at least equimolar amounts, with respect tothat reactant not used in excess, e.g. in an amount of from 1 to 5 molper mol of the reactant not used in excess, in particular 1 to 4 mol permol of the reactant not used in excess, specifically 1.1 to 3 mol permol of the reactant not used in excess. If the reactants are used inequimolar ratio, the above amounts of catalyst apply of course to eitherof the reactants.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C.

The reaction can be carried out by standard proceedings for carboxamideformation, e.g. by mixing all reagents, water and the cellulosederivative and reacting them at the desired temperature. Alternativelythe reagents can be added gradually, especially in the case of acontinuous or semicontinuous process.

Workup proceedings will be described below, as they are similar for mostreactions.

Sulfonamide Bond Formation

For the synthesis of sulfonamides, generally a sulfonic acid or aderivative of a sulfonic acid capable of amide formation, for instance asulfonic acid halide, anhydride or ester, is reacted with a primary orsecondary amine:

R¹, R², R³ and X are as defined above in context with the carboxamidebond formation, except for R¹ here not being H and except of X being inthe anhydride alternative O—S(O)₂—R^(1′) instead of O—C(O)—R^(1′). Theabove remarks on how to carry out the reaction, especially the variousmethods depending on X, apply here, too.

In a particular embodiment of the present invention, a sulfonic acidhalide (X=halogen), especially a sulfonic acid chloride (X=Cl), isreacted with a primary or secondary amine in the presence of a base.Suitable bases are those listed above in context with the Suzukireaction. In particular the base is an alkali metal hydroxide, e.g.LiOH, NaOH or KOH, an alkali metal carbonate, e.g. Li₂CO₃, Na₂CO₃, K₂CO₃or Cs₂CO₃, or a silanolate, e.g. sodium or potassium trimethylsilanolate((CH₃)₃SiO⁻) or triisopropylsilanolate ((CH(CH₃)₂)₃SiO⁻).

In a particular embodiment, R¹ is alky or aryl, where the alkyl or arylgroup may be substituted as described above. Specifically, R¹ is phenylwhich may be substituted as described above and in particular by one ormore R¹⁵, where R¹⁵ is as defined in context with the Suzuki reaction.

In a particular embodiment, R² is H and R³ is alky or aryl, where thealkyl or aryl group may be substituted as described above, or R² and R³form together with the nitrogen atom they are bound to a mono-, bi- orpolycyclic ring, such as piperidine-1-yl, 1-alkyl-piperazin-4-yl,morpholinyl, pyrrolidin-1-yl, pyrrolin-1-yl, pyrrol-1-yl, indolin-1-yl,indol-1-yl etc. Specifically, R³ is C₁-C₁₀-alkyl which may carry aphenyl ring, which may in turn be substituted as described above and inparticular by one or more R¹⁵, or is C(O)R¹³, or is N(R^(12a))R^(12b),where R^(12a), R^(12b), R¹³ and R¹⁵ are as defined in context with theSuzuki reaction; or, specifically, R² and R³ form together with thenitrogen atom they are bound to a mono-, bi- or polycyclic ring, such aspiperidine-1-yl, 1-alkyl-piperazin-4-yl, morpholinyl, pyrrolidin-1-yl,pyrrolin-1-yl, pyrrol-1-yl, indolin-1-yl, indol-1-yl etc. SpecificallyR¹³ is C₁-C₄-alkyl. Specifically R^(12a) and R^(12b) are bothC₁-C₁₀-alkyl or are both H, where however one of the hydrogen atoms isreplaced by a protective group, such as boc, benzyl or F-moc.

The acid (derivative) and the amine can be used in a molar ratio of from10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5. In particular,they are used in a molar ratio of from 3:1 to 1:3, more particularly 2:1to 1:2 and specifically from 1.5:1 to 1:1.5.

If the amidation is carried out in the presence of a base, this isgenerally used in excess, i.e. in overstoichiometric amounts withrespect to that reactant not used in excess, e.g. in an amount of from1.5 to 5 mol per mol of the reactant not used in excess, in particular1.5 to 4 mol per mol of the reactant not used in excess, specifically1.5 to 3 mol per mol of the reactant not used in excess. If thereactants are used in equimolar ratio, the above amounts of base applyof course to either of the reactants.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 20° C. to 50° C. andvery specifically from 20° C. to 30° C.

The reaction can be carried out by standard proceedings for sulfonamideformation, e.g. by mixing all reagents, water and the cellulosederivative and reacting them at the desired temperature. Alternativelythe reagents can be added gradually, especially in the case of acontinuous or semicontinuous process.

Workup proceedings will be described below, as they are similar for mostreactions.

In another particular embodiment of the invention, the organic reactionis the introduction of a protective group.

Introduction of Protective Groups

In certain reactions, some functional groups, such as NH, NH₂, OH, SH orCOOH, have to be protected in order to avoid their (competitive)reaction.

Protection of Primary or Secondary Amino Groups

Protective groups for amino groups are well known. Examples areC₁-C₄-alkylcarbonyl (e.g. acetyl, tert-butylcarbonyl),C₁-C₄-haloalkylcarbonyl (e.g. trifluoroacetyl), C₃-C₄-alkenylcarbonyl(e.g. allylcarbonyl), C₁-C₄-alkoxycarbonyl (e.g.tert-butyloxycarbonyl=Boc), C₁-C₄-haloalkoxycarbonyl,C₃-C₄-alkenyloxycarbonyl (e.g. allyloxycarbonyl=Alloc),fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Z or Cbz),C₁-C₄-alkylaminocarbonyl, di-(C₁-C₄-alkyl)-aminocarbonyl,C₁-C₄-alkylsulfonyl, C₁-C₄-haloalkylsulfonyl, benzyl or substitutedbenzyl (e.g. p-methoxybenzyl (=Mpm) or 2,3-dimethoxybenzyl). Suitableprotective groups are for example described in T. Greene and P. Wuts,Protective Groups in Organic Synthesis (3^(rd) ed.), John Wiley & Sons,NY (1999). The (oxy)carbonyl and sulfonyl groups can be principallyintroduced in accordance with the above-described amidation reactions,especially via reaction of the amine with the respective (oxy)carboxylicchloride, (active) ester or anhydride or with the respective sulfonylchloride, (Oxy)Carbonyl can moreover be introduced via reaction with therespective succinimidoester. The anhydride is generally a symmetricanhydride. With respect to the terms “active ester” and “symmetricanhydride”, reference is made to the above-described amidationreactions. The reagents used for introducing the protective group, suchas boc anhydride for introducing boc, are termed in the following“protective group precursors”. (Oxy)carbonyl means carbonyl oroxycarbonyl.

Suitable (oxy)carbonylation/sulfonylation reagents (i.e. protectivegroup precursors for introducing (oxy)carbonyl and sulfonyl protectivegroups) are well known. For example, boc is generally introduced viareaction with boc anhydride. Z is generally also introduced via therespective anhydride. Alkyl carbonyl groups are also often introducedvia reaction with the symmetric anhydride, e.g. with acetanhydride or2,2-dimethylacetanhydride. Benzyl or substituted benzyl is generallyintroduced via reaction of the amine with (substituted) benzyl chlorideor bromide.

If the carbonylation/sulfonylation reagent is an acid chloride or ananhydride, the protection reaction is generally carried out in thepresence of a base. Suitable bases are those listed in context with theSuzuki reaction.

In a particular embodiment, a primary or secondary amine R¹(R²)NH isreacted with an alkylcarbonyl (e.g. acetyl), C₁-C₄-haloalkylcarbonyl(e.g. trifluoroacetyl), C₃-C₄-alkenylcarbonyl (e.g. allylcarbonyl),C₁-C₄-alkoxycarbonyl (e.g. tert-butyloxycarbonyl=Boc),C₁-C₄-haloalkoxycarbonyl, C₃-C₄-alkenyloxycarbonyl (e.g.allyloxycarbonyl=Alloc), fluorenylmethoxycarbonyl (Fmoc) orbenzyloxycarbonyl (Z or Cbz) chloride, anhydride or succinimidoester.The anhydride is generally a symmetric anhydride. As said, if a chlorideor an anhydride is used, the reaction is generally carried out in thepresence of a base.

Specifically, a primary or secondary amine R¹(R²)NH is reacted with bocanhydride.

In another specific embodiment, a primary or secondary amine R¹(R²)NH isreacted with Z anhydride (dibenzyl dicarbonate).

In another specific embodiment, a primary or secondary amine R¹(R²)NH isreacted with acetic anhydride.

R¹ and R², independently of each other, are alkyl, alkenyl,alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenylcycloalkynyl,polycarbocyclyl, heterocyclyl, aryl or heteroaryl, where R¹ mayadditionally be hydrogen; or R¹ and R², together with the nitrogen atomthey are bound to, form a mono-, bi- or polycyclic heterocyclic ring,which, apart from the compulsory nitrogen atom, may contain 1, 2 or 3 or4 further heteroatoms or heteroatom groups selected from the groupconsisting of N, O, S, NO, SO or SO₂ as ring members.

The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl,heteroaryl groups R¹ and R², as well as the mono-, bi- or polycyclicheterocyclic ring formed by R¹ and R² together with the nitrogen atomthey are bound to, can be substituted by one or more substituents.Suitable substituents for the alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl andheteroaryl groups R¹ and R² correspond to those listed above in contextwith substituents on the alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl orheteroaryl groups R¹ and R² in the Suzuki coupling. Suitablesubstituents for heterocyclyl groups R¹ and R² and for the the mono-,bi- or polycyclic heterocyclic ring formed by R¹ and R² together withthe nitrogen atom they are bound to correspond to those listed above incontext with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl,mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroarylgroups R¹ and R² in the Suzuki coupling.

In these substituents, however, all functional groups have to be lessreactive than the desired reaction site towards the specific protectivegroup precursor.

In a specific embodiment, R¹ is hydrogen and R² is an alkyl, alkenyl,alkynyl, cycloalkyl, polycarbocyclyl, heterocyclyl, aryl or heteroarylgroup, where the alkyl, alkenyl, alkynyl, cycloalkyl, polycarbocyclyl,heterocyclyl, aryl or heteroaryl group may carry one or moresubstituents, where suitable substituents correspond to those listedabove in context with substituents on the alkyl, alkenyl, alkynyl,cycloalkyl, polycarbocyclyl, heterocyclyl, aryl and heteroaryl groups R¹and R² in the Suzuki coupling (suitable substituents for heterocyclylgroups correspond to those listed above in context with substituents onthe cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling).

More specifically, R¹ is hydrogen and R² is heterocyclyl, in particulara 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10- or 11-membered monocyclic or bicyclicsaturated, partially unsaturated or maximally unsaturated heterocyclic(inclusive heteroaromatic) ring which may carry one or more substituentsas defined above. In particular, the heterocyclyl ring R² is aheteroaryl group. Heteroaryl groups R² are in particular selected fromthe group consisting of 5- or 6-membered heteroaromatic monocyclic ringsand 9- or 10-membered heteroaromatic bicyclic rings containing 1, 2, 3or 4 heteroatoms selected from the group consisting of N, O and S asring members. Mono- or bicyclic heteroaryl groups R² are for examplefuranyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl, isoxazoyl,thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl,[1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls,pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl,isoquinolinyl, quinazalinyl and the like. More particularly, they arefor example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl,1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl,1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl,1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl,1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl,4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl,1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl,1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl,indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromaticbicyclic rings shown below in the “general definitions”.

Suitable substituents on the heterocyclyl ring R² are e.g. selected fromthe group consisting of halogen, cyano, nitro, OH, SH, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl, C₂-C₆-alkynyl,C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl,C₃-C₈-cycloalkyl-C₁-C₆-alkyl, C₃-C₈-halocycloalkyl-C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl,C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members and a 9- or 10-memberedheteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members, wherephenyl and the heteroaromatic rings may carry one or more substituentsselected from the group consisting of fluorine, cyano, nitro, OH, SH,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino. Specifically, the substituents on theheterocyclyl ring R² are selected from the group consisting of halogen,cyano, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino. In case of amino and C₁-C₄-alkylaminosubstituents, these may also react with the protective agent.

In another specific embodiment, R¹ is hydrogen and R² is aryl,specifically phenyl, which may carry one or more substituents as definedabove. Suitable substituents on the aryl group R² are e.g. selected fromthe group consisting of halogen, cyano, nitro, OH, SH, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl, C₂-C₆-alkynyl,C₂-C₆-haloalkynyl, C₁-C₄-alkyl substituted by a radical selected fromthe group consisting of CN, OH, SH, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl,C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl,formyl, C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl,C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members and a 9- or 10-memberedheteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members, wherephenyl and the heteroaromatic rings may carry one or more substituentsselected from the group consisting of fluorine, cyano, nitro, OH, SH,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino; C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl,C₃-C₈-cycloalkyl-C₁-C₆-alkyl, C₃-C₈-halocycloalkyl-C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl,C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members and a 9- or 10-memberedheteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members, wherephenyl and the heteroaromatic rings may carry one or more substituentsselected from the group consisting of fluorine, cyano, nitro, OH, SH,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino. Specifically, the substituents on the aryl groupR² are selected from the group consisting of halogen, cyano,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₄-alkyl substituted by a radicalselected from the group consisting of CN, OH, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl,C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino and phenyl; C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members and a 9- or 10-memberedheteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members, wherephenyl and the heteroaromatic rings may carry one or more substituentsselected from the group consisting of fluorine, cyano, nitro, OH, SH,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl,C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl,C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylaminoand di-(C₁-C₄-alkyl)amino. Very specifically, the substituents on thearyl group R² are selected from the group consisting of halogen, cyano,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₄-alkyl substituted by a radicalselected from the group consisting of CN, OH, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl,C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl, and phenyl;C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members and a 9- or 10-memberedheteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members, wherephenyl and the heteroaromatic rings may carry one or more substituentsselected from the group consisting of fluorine, cyano, nitro, OH, SH,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl,C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl,C₁-C₄-alkoxycarbonyl and C₁-C₄-haloalkoxycarbonyl.

In another specific embodiment, R¹ is hydrogen and R² is polycarbocyclylwhich may carry one or more substituents as defined above; preferably a9- to 10-membered condensed saturated or partially unsaturatedcarbocyclic ring system, in particular selected from indanyl,tetrahydronaphthyl, hexahydronaphthyl, octahydronaphthyl anddecahydronaphthyl, which may carry one or more substituents as definedabove. In indanyl and tetrahydronaphthyl the attachment point to N is onthe nonaromatic ring moiety. Suitable substituents on thepolycarbocyclyl ring R² are e.g. selected from the group consisting ofhalogen, cyano, nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₂-C₆-alkenyl, C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl,C₁-C₄-alkyl substituted by a radical selected from the group consistingof CN, OH, SH, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, formyl, C₁-C₄-alkylcarbonyl,C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl,amino, C₁-C₄-alkylamino, di-(C₁-C₄-alkyl)amino, phenyl, a 5- or6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4heteroatoms selected from the group consisting of N, O and S as ringmembers and a 9- or 10-membered heteroaromatic bicyclic ring containing1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O andS as ring members, where phenyl and the heteroaromatic rings may carryone or more substituents selected from the group consisting of fluorine,cyano, nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino; C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl,C₃-C₈-cycloalkyl-C₁-C₆-alkyl, C₃-C₈-halocycloalkyl-C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio, C₁-C₆-haloalkythio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl,C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members and a 9- or 10-memberedheteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members, wherephenyl and the heteroaromatic rings may carry one or more substituentsselected from the group consisting of fluorine, cyano, nitro, OH, SH,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino.

In another specific embodiment, R¹ and R², together with the nitrogenatom they are bound to, form a mono-, bi- or polycyclic heterocyclicring, which, apart from the compulsory nitrogen atom, may contain 1, 2or 3 or 4 further heteroatoms or heteroatom groups selected from thegroup consisting of N, O, S, NO, SO or SO₂ as ring members. Veryspecifically, R¹ and R², together with the nitrogen atom they are boundto, form a mono- or bicyclic heterocyclic ring, specifically a 3-, 4-,5-, 6-, 7-, 8-, 9-, 10- or 11-membered mono- or bicyclicsaturated,partially zunsaturated or maximally unsaturated heterocyclic ring,which, apart from the compulsory nitrogen atom, may contain 1 or 2further heteroatoms or heteroatom groups selected from the groupconsisting of N, O, S, NO, SO or SO₂ as ring members.

The amine and the protective group precursor can be used in a molarratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5. Inparticular, they are used in a molar ratio of from 3:1 to 1:3, moreparticularly 2:1 to 1:2 and specifically from 1.5:1 to 1:1.5.

If the reaction is carried out in the presence of a base, this isgenerally used in excess, i.e. in overstoichiometric amounts withrespect to that reactant not used in excess, e.g. in an amount of from1.1 to 5 mol per mol of the reactant not used in excess, in particular1.1 to 4 mol per mol of the reactant not used in excess, specifically1.1 to 3 mol per mol of the reactant not used in excess. If thereactants are used in equimolar ratio, the above amounts of base applyof course to either of the reactants.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 20° C. to 50° C. andvery specifically from 20° C. to 30° C.

The reaction can be carried out by standard proceedings for introducingthe respective protective group, e.g. by mixing all reagents, water andthe cellulose derivative and reacting them at the desired temperature.Alternatively the reagents can be added gradually, especially in thecase of a continuous or semicontinuous process.

Workup proceedings will be described below, as they are similar for mostreactions.

Deprotection Reaction

In another particular embodiment of the invention, the organic reactionis a deprotection reaction, i.e. the removal of a protective group. Thespecific deprotection conditions depend on the protective group to beremoved and are known in the art. They are described, for example, in T.Greene and P. Wuts, Protective Groups in Organic Synthesis (3^(rd) ed.),John Wiley & Sons, NY (1999).

Deprotection of Protected Primary or Secondary Amines

Suitable and preferred protective groups and suitable and preferredamines are described above. Conditions for deprotecting primary orsecondary amines depend on the specific protective group and thesusceptibility of the amine to undergo undesired reactions duringdeprotection. Generally they involve a hydrolysis or a hydrogenolysis.For instance, boc is removed via hydrolysis under acidic conditionsusing e.g. HCl, trifluoroacetic acid or toluenesulfonic acid. Otheroxycarbonyl protective groups, such as Fmoc, can be removed via basichydrolysis, e.g. with NaOH or an organic base, such as piperidine orpyridine. Cbz can be removed via hydrogenolysis, mostly catalyzed withPd or Pt, or using Na/NH₃, or with trimethylsilyl iodide, or viareaction with strong acids, e.g. HBr/acetic acid. Alloc is generallyremoved metal-catalyzed with Ni or Pt. Carbonyl protective groups, e.g.acetyl, are removed via acidic or basic hydrolysis. Generally, thisrequires harsher conditions, such as heating to reflux. Benzyl isgenerally removed via hydrogenolysis, mostly catalyzed with Pd or Pt.

In another particular embodiment of the invention, the organic reactionis a nucleophilic substitution reaction.

Nucleophilic Substitution Reactions

Nucleophilic substitution is a fundamental class of reactions in whichan electron-rich nucleophile selectively bonds with or attacks thepositive or partially positive charge of an atom or a group of atoms toreplace a leaving group; the positive or partially positive atom beingtermed electrophile: Nu: +R-LG→R-Nu+LG:

“Nu” is the nucleophile; “:” is an electron pair; “LG” is a leavinggroup and “R” is a hydrocarbyl radical, e.g. an aliphatic,cycloaliphatic, aromatic, hetercyclic or heteroaromatic radical.

The electron pair (:) from the nucleophile (Nu) attacks the substrate(R-LG) forming a new bond, while the leaving group (LG) departs with anelectron pair. The principal product in this case is R-Nu. Thenucleophile may be electrically neutral or negatively charged, whereasthe substrate is typically neutral or positively charged.

Advantageously, the leaving group forms an anion of low energy or anuncharged molecule or can be removed by an energetically advantageousprocess. Therefore, the leaving group is frequently a halide, asulfonate or a diazonium group.

Nucleophilic substitution reactions form one of the largest classes oforganic reactions and are therefore often treated in subclassesdepending on the functional group formed, on the product formed or onthe substrate used. For instance, many carbonyl reactions arenucleophilic substitutions, e.g. ester bond formations, transesterifications, hydrolyses, amide bond formation or carbonyl halideformation; ether and thioether bond formation, amine bond formation etc.The method of the invention can be applied to all types of nucleophilicsubstitutions, but given the vastness of this reaction type, only somerepresentative examples are discussed in more detail.

One subclass of nucleophilic substitution is nucleophilic aromaticsubstitution. Thus, in particular embodiment of the invention, theorganic reaction, to be more precise the nucleophilic substitutionreaction, is a nucleophilic aromatic substitution reaction.

Nucleophilic Aromatic Substitution Reactions

Nucleophilic aromatic substitution is a substitution reaction in which anucleophile displaces a good leaving group on an aromatic or aheteroaromatic ring. Due to the system of conjugated double bonds,aromatic compounds (especially carboaromatic compounds and electron-richheteroaromatic compounds) are Lewis bases and thus the exchange ofsubstituents by nucleophilic reagents is distinctly more difficult thanelectrophilic substitutions. It is essential that the leaving groupforms an anion of low energy or an uncharged molecule or can be removedby an energetically advantageous process. Therefore, the leaving groupis mostly a halide, a sulfonic acid group or a diazonium group innon-activated (hetero)aromatic compounds. Nucleophilic aromaticsubstitution on carboaromatic rings (phenyl, naphthyl etc.) is eased ifthe aromatic ring is activated, i.e. contains substituents with a -Meffect in ortho and/or para position to the carbon atom carrying theleaving group. Substituents with a -M effect are for example thediazonium, nitroso, nitro, cyano, formyl, or acetyl group. In this case,also less favoured leaving groups can react; e.g. even hydrogen atomscan be replaced. Electron-poor heteroaromatic rings, like the 6-memberedheteroaromatic compounds (pyridine, pyridazine, pyrimidine, pyrazine,the triazines) or quinoline, also undergo readily nucleophilicsubstitution, even with poor leaving groups, like the hydrogen atom.

Suitable nucleophiles are in particular Lewis bases, like water,alcohols, thiols or primary or secondary amines.

The reaction is often carried out in the presence of a base, especiallyif the leaving group is a halide and the nucleophile is water, analcohol, a thiol or a primary or secondary amine.

In a particular embodiment of the present invention a mono-, bi- orpolycyclic aromatic or heteroaromatic halide R¹—X is reacted with analcohol R²—OH, a thiol R²—SH, a primary amine R³NH₂ or a secondary amineR³(R⁴)NH. R¹ is a mono-, bi- or polycyclic aryl or heteroaryl group; Xis a halide, especially F or Cl, and R², R³ and R⁴ are independently ofeach other an alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl orheteroaryl group. The alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl,heterocyclyl, aryl, heteroaryl groups R¹, R², R³ and R⁴ can besubstituted by one or more substituents. Suitable substituentscorrespond to those listed above in context with substituents on thealkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling. Suitable substituents for heterocyclylgroups R¹, R², R³ and R⁴ correspond to those listed above in contextwith substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling.

In these substituents, however, all functional groups have to be lessreactive than the desired reaction sites for the desired reaction (i.e.less reactive than X in R¹—X towards R²—OH, R²—SH, R³NH₂ or R³(R⁴)NH;less reactive than OH, SH, NH₂ or NH in R²—OH, R²—SH, R³NH₂ andR³(R⁴)NH, respectively, towards R¹—X).

In a particular embodiment the aryl group R¹ is mono-, bi- or tricyclicand is specifically selected from the group consisting of phenyl andnaphthyl; and the heteroaryl group R¹ is in particular mono-, bi- ortricyclic and is specifically selected from the group consisting of 5-or 6-membered heteroaromatic monocyclic rings and 9- or 10-memberedheteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members. Mono-or bicyclic aryl or heteroaryl groups R¹ are for example phenyl,naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl,isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl,[1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls,pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl,isoquinolinyl, quinazalinyl and the like. More particularly, they arefor example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl,1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl,1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl,1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl,1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl,4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl,1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl,1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl,indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,quinolinyl, isoquinolinyl, quinazalinyl, chromanyl bound via the 5-, 6-,7- or 8-position and other heteroaromatic bicyclic rings shown below inthe “general definitions”.

The aryl and heteroaryl groups R¹ can carry one or more substituents,e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2substituents. Suitable substituents are listed above in context witharyl and heteroaryl groups R¹ and R² in the Suzuki reaction. In aparticular embodiment, the substituents on the aryl and heteroarylgroups R¹ are selected from the group consisting of halogen, cyano,nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₁-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, where the alkyl groups in alkylamino anddialkylamino can in turn be substituted by one or more substituentsselected from the group consisting of CN, OH, SH, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members and a 9- or 10-memberedheteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members, wherephenyl and the heteroaromatic rings may carry one or more substituentsselected from the group consisting of fluorine, cyano, nitro, OH, SH,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino; phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members and a 9- or 10-memberedheteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members, wherephenyl and the heteroaromatic rings may carry one or more substituentsselected from the group consisting of halogen, cyano, nitro, OH, SH,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino. Specifically, the substituents on the aryl andheteroaryl groups R¹ are selected from the group consisting of halogen,cyano, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl andC₁-C₄-haloalkoxycarbonyl. Especially in the case of the carboaromatis,e.g. the above-listed phenyl, naphthyl, anthracenyl and phenanthrenylgroups, it is expedient for these to carry a substituent with -M effectin ortho- and/or para-position to X, e.g. a nitro group. Analogously,electron-rich heterocyclic rings, like the 5-membered heteroaromaticrings, especially pyrrole, carry advantageously a -M substituent.

Especially, the mono-, bi- or polycyclic aryl or heteroaryl groups R¹are selected from the group consisting of phenyl carrying in ortho-and/or para-position to X a substituent with -M effect, specifically anitro group, from the 6-membered heteroaromatic groups, i.e. frompyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl and1,3,5-triazinyl, and from quinolinyl. Specifically, the mono-, bi- orpolycyclic aryl or heteroaryl groups R¹ are selected from the groupconsisting of phenyl carrying in ortho- and/or para-position to X asubstituent with -M effect, specifically a nitro group; pyridyl andpyrimidyl. The 6-membered heteroaromatic groups and quinolinyl may carryone or more substituents, e.g. those described above, for example thosementioned as R¹⁵ in the Suzuki reaction.

In particular, R², R³ and R⁴ are independently of each other an alkyl oraryl group, where the alkyl group may carry an aryl group, where thearyl groups may carry one or more substituents, e.g. those describedabove, for example those mentioned as R¹⁵ in the Suzuki reaction.Specifically, R² is an aryl group, in particular phenyl or naphthyl,which may carry one or more substituents, e.g. those described above,for example those mentioned as R¹⁵ in the Suzuki reaction. Specifically,R⁴ is hydrogen and R³ is C₁-C₄-alkyl, where alkyl may carry one or morearyl substituents, specifically one phenyl substituent, where the arylsubstituents may in turn carry one or more substituents, e.g. thosedescribed above, for example those mentioned as R¹⁵ in the Suzukireaction, specifically CN, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy orC₁-C₄-alkoxy.

The reaction is often carried out in the presence of a base, especiallyif the leaving group is a halide and the nucleophile is water, analcohol, a thiol or a primary or secondary amine. Suitable bases arethose listed above in context with the Suzuki reaction.

The reaction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 20° C. to 50° C. andvery specifically from 20° C. to 30° C.

The (hetero)aromatic compound to be substituted and the nucleophile canbe used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 orfrom 5:1 to 1:5. Preferably they are used in a molar ratio of from 3:1to 1:3, in particular 2:1 to 1:2 and specifically 1.5:1 to 1:1.5.

The base is generally used in at least equimolar amount, with respect tothat reactant not used in excess, e.g. in an amount of from 1 to 5 molper mol of the reactant not used in excess, in particular 1 to 3 mol permol of the reactant not used in excess, specifically 1 to 2 mol per molof the reactant not used in excess. If the reactants are used inequimolar ratio, the above amounts of base apply of course to either ofthe reactants.

The reaction can be carried out by standard proceedings for nucleophilicaromatic substitutions, e.g. by mixing all reagents, inclusive base,water and the cellulose derivative, and reacting them at the desiredtemperature. Alternatively the reagents can be added gradually,especially in the case of a continuous or semicontinuous process.

Workup proceedings will be described below, as they are similar for mostreactions.

In another particular embodiment of the present invention a mono-, bi-or polycyclic aromatic or heteroaromatic alcohol R¹—OH, thiol R¹—SH,primary amine R¹NH₂ or a secondary amine R¹(R⁴)NH is reacted with ahalide R²—X, resulting in a ether R¹—O—R², thioether R¹—S—R², secondaryamine R¹—N(H)—R² or tertiary amine R¹—N(R⁴)—R². R¹, R² and R⁴ are asdefined above. The reaction conditions are also as described above incontext with the reaction of an aromatic or heteroaromatic halide R¹—Xwith an alcohol R²—OH, thiol R²—SH, primary amine R³NH₂ or a secondaryamine R³(R⁴)NH.

Another subclass of nucleophilic substitution is ether bond formation.Thus, in particular embodiment of the invention, the organic reaction,to be more precise the nucleophilic substitution reaction, is anetherification reaction.

Ether Bond Formation

In this reaction class, generally a hydroxyl compound R¹—OH is reactedwith a compound R²-LG, wherein LG is leaving group, such as a halide, ahydroxyl group, a sulfonate group or, especially in aromatic orheteroaromatic groups R², a diazonium group. R¹ and R² can be anyaliphatic, cycloaliphatic, heterocyclic, aromatic or heteroaromaticgroup. If one of R¹ and R² or both are aromatic or heteroaromatic,reference is made to the above remarks made in context with nucleophilicaromatic substitution.

R¹ and R² are preferably independently alkyl, alkenyl, alkapolyenyl,alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl,heterocyclyl, aryl or heteroaryl. The alkyl, alkenyl, alkapolyenyl,alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl,heterocyclyl, aryl, heteroaryl groups can be substituted by one or moresubstituents. Suitable substituents for alkyl, alkenyl, alkapolyenyl,alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl andheteroaryl correspond to those listed above in context with substituentson the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling. Suitable substituents for heterocyclylgroups correspond to those listed above in context with substituents onthe cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling.

In these substituents, however, all functional groups have to be lessreactive than the desired reaction sites for the desired reaction.

In a particular embodiment R¹ is aryl or hetaryl, where preferably, thearyl group R¹ is mono-, bi- or tricyclic and is specifically selectedfrom the group consisting of phenyl and naphthyl; and the heteroarylgroup R¹ is in particular mono-, bi- or tricyclic and is specificallyselected from the group consisting of 5- or 6-membered heteroaromaticmonocyclic rings and 9- or 10-membered heteroaromatic bicyclic ringscontaining 1, 2, 3 or 4 heteroatoms selected from the group consistingof N, O and S as ring members. Mono- or bicyclic aryl or heteroarylgroups R¹ are for example phenyl, naphthyl, furanyl, thienyl, pyrrolyl,pyrazolyl, imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl,[1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls,the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl,pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl,benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. Moreparticularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl,3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl,1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl,1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl,1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl,1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl,1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl,4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl,3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl,1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl,1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl,benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl,quinazalinyl, chromanyl bound via the 5-, 6-, 7- or 8-position and otherheteroaromatic bicyclic rings shown below in the “general definitions”.Specifically, R¹ is chromanyl bound via the 5-, 6-, 7- or 8-position.

The aryl and heteroaryl groups R¹ can carry one or more substituents,e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2substituents. Suitable substituents are listed above in context witharyl and heteroaryl groups R¹ and R² in the Suzuki reaction. In aparticular embodiment, the substituents on the aryl and heteroarylgroups R¹ are selected from the group consisting of halogen, cyano,nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, (protected) amino, (protected)C₁-C₄-alkylamino, di-(C₁-C₄-alkyl)amino, where the alkyl groups inalkylamino and dialkylamino can in turn be substituted by one or moresubstituents selected from the group consisting of CN, OH, SH,C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl,C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl,formyl, C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl,C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members and a 9- or 10-memberedheteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members, wherephenyl and the heteroaromatic rings may carry one or more substituentsselected from the group consisting of fluorine, cyano, nitro, OH, SH,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,C₁-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino;

phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1,2, 3 or 4 heteroatoms selected from the group consisting of N, O and Sas ring members and a 9- or 10-membered heteroaromatic bicyclic ringcontaining 1, 2, 3 or 4 heteroatoms selected from the group consistingof N, O and S as ring members, where phenyl and the heteroaromatic ringsmay carry one or more substituents selected from the group consisting ofhalogen, cyano, nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₂-C₆-alkenyl, C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl,C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, (protected) amino, (protected)C₁-C₄-alkylamino and di-(C₁-C₄-alkyl)amino. Specifically, thesubstituents on the aryl and heteroaryl groups R¹ are selected from thegroup consisting of halogen, cyano, C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkythio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, protected amino, (protected) C₁-C₄-alkylaminoand di-(C₁-C₄-alkyl)amino. Very specifically, the substituents on thearyl and heteroaryl groups R¹ are selected from the group consisting ofprotected amino, (protected) C₁-C₄-alkylamino and di-(C₁-C₄-alkyl)amino.

In particular, R⁴ is C₁-C₄-alkyl, where alkyl may carry one or more arylsubstituents, specifically one phenyl substituent, where the arylsubstituents may in turn carry one or more substituents, e.g. thosedescribed above, for example those mentioned as R¹⁵ in the Suzukireaction, specifically F, Cl, CN, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxy or C₁-C₄-alkoxy.

Another subclass of nucleophilic substitution is ester bond formation(esterification) and the reverse reaction (ester hydrolysis). Thus, inparticular embodiment of the invention, the organic reaction, to be moreprecise the nucleophilic substitution reaction, is an esterificationreaction or an ester hydrolysis.

Esterifications and Ester Hydrolysis

For the synthesis of carboxylic esters, generally a carboxylic acid or aderivative of a carboxylic acid capable of ester bond formation, forinstance an acid halide or acid anhydride, is reacted with a hydroxylcompound:

In an ester hydrolysis the inverse reaction takes place: An ester isreacted (formally) with water to the respective carboxylic acid:

R¹ and R² are independently alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl,heterocyclyl, aryl or heteroaryl, where R¹ can also be H; X is OH, OR⁴,O—C(O)—R^(1′) or a halogen atom, where R⁴ is alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl or heteroaryl and R^(1′) is independentlydefined as R¹. Alternatively, X is another common leaving group, forexample thiophenyl or imidazolyl.

The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl,heteroaryl groups can be substituted by one or more substituents.Suitable substituents for alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl andheteroaryl correspond to those listed above in context with substituentson the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling. Suitable substituents for heterocyclylgroups correspond to those listed above in context with substituents onthe cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling. If however these groups carrysubstituents which can compete in the esterification reaction, e.g.further OH groups, it is expedient to protect these groups before theesterification reaction. For example, OH groups can be protected bystandard O-protective groups, such as silyl groups. Suitable protectivegroups are for example described in T. Greene and P. Wuts, ProtectiveGroups in Organic Synthesis (3^(rd) ed.), John Wiley & Sons, NY (1999).Alike, when these groups carry a COY substituent, where Y is as definedas X, Y has to be converted into a group which is less reactive than Xversus the hydroxy compound in the esterification reaction or versuswater in the hydrolysis. For instance, if X is OH, Y has to be convertedinto an alkoxy group, such as methoxy or ethoxy.

Esterification can be carried out by reacting the carboxylic acid (X=OH)with the hydroxy compound under heating and removal of reaction water,but is preferably carried out by activation of the carboxylic acid with,e.g. oxalylchloride [(COCl)₂] or thionylchloride (SOCl₂) to therespective acid chloride (X=Cl), followed by reaction with the hydroxycompound.

Alternatively, the ester R¹—COOR⁴ is a so-called active ester, which isobtained in a formal sense by the reaction of the acid R¹—COOH with anactive ester-forming alcohol, such as p-nitrophenol,N-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide or OPfp(pentafluorophenol).

The acid anhydride R¹—CO—O—OC—R^(1′) is either a symmetric anhydrideR¹—CO—O—OC—R¹ (R^(1′)═R¹) or an asymmetric anhydride in which—O—OC—R^(1′) is a group which can be displaced easily by the hydroxycompound. Suitable acid derivatives with which the carboxylic acidR¹—COOH can form suitable mixed anhydrides are, for example, the estersof chloroformic acid, for example isopropyl chloroformate and isobutylchloroformate, or of chloroacetic acid.

If X is a halogen atom, the reaction is generally carried out in thepresence of a base. Suitable bases are those listed above in contextwith the Suzuki reaction.

In ester hydrolysis, generally a base is used and elevated temperatureis applied, e.g. from 30 to 70° C. or from 40 to 60° C. or from 45 to60° C. Suitable bases are those listed above in context with the Suzukireaction, especially the inorganic bases, specifically alkali metalhydroxides, such as NaOH or KOH.

In a particular embodiment, R¹ is heterocyclyl which may be substitutedas described above. Specifically, R¹ is a saturated 3-, 4-, 5-, 6- or7-membered heterocyclic ring containing 1, 2 or 3 heteroatoms orheteroatom groups selected from N, O, S, NO, SO and SO₂ as ring members,where the heterocyclic ring may be substituted as described above.Specifically, the heterocyclic ring may carry one or more substituentsselected from alkyl, cycloalkyl, polycarbocyclyl, aryl and hetaryl whichmay in turn be substituted. Very specifically, the heterocyclic ring maycarry one or more substituents selected from C₁-C₄-alkyl,C₃-C₈-cycloalkyl and a bicyclic carbocyclic ring containing 8, 9 or 10carbon atoms as ring members, such as indanyl, indenyl, dihydronaphthyl,terahydronaphthyl, hexahydronaphthyl, octahydronaphthyl or decalin.

In the esterification, the acid (derivative) and the hydroxy compoundcan be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7or from 5:1 to 1:5. In particular, they are used in a molar ratio offrom 3:1 to 1:3, more particularly 2:1 to 1:2 and specifically from1.5:1 to 1:1.5.

In the hydrolysis reaction, water is generally used in excess.

The esterification reaction is preferably carried out at from 10° C. to60° C., in particular from 20° C. to 55° C.

Hydrolysis is preferably carried at at elevated temperature, e.g. from30 to 70° C. or in particular from 40 to 60° C. or specifically from 45to 60° C.

The esterification reaction can be carried out by standard proceedingsfor ester bond formation, e.g. by mixing all reagents, water and thecellulose derivative and reacting them at the desired temperature.Alternatively the reagents can be added gradually, especially in thecase of a continuous or semicontinuous process.

The hydrolysis reaction can be carried out by standard proceedings forester bond hydrolysis.

Workup proceedings will be described below, as they are similar for mostreactions.

Another class of nucleophilic substitution is amine bond formation inwhich an amine is reacted with a compound carrying a leaving group.

Amination

In this context, “amination” refers only to nucleophilic substitution ofa leaving group by an amino group. Suitable amines are primary andsecondary amines, and also ammonia can be used. Reaction conditions andsuitable reactants correspond analogously to those listed above incontext with etherification reactions. Thus, generally an amino compoundNHR³R⁴ is reacted with a compound R²-LG, wherein LG is leaving group,such as a halide, a hydroxyl group or a sulfonate group. R³ and R⁴,independently of each other, can be H or any aliphatic, cycloaliphatic,heterocyclic, aromatic or heteroaromatic group. If one of R³, R⁴ and R²or two thereof or all three are aromatic or heteroaromatic, reference ismade to the above remarks made in context with nucleophilic aromaticsubstitution.

Preferably, R³ is H and R⁴ and R² are preferably independently alkyl,alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, heterocyclyl, aryl or heteroaryl. The alkyl, alkenyl,alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, heterocyclyl, aryl, heteroaryl groups can besubstituted by one or more substituents. Suitable substituents foralkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroarylcorrespond to those listed above in context with substituents on thealkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling. Suitable substituents for heterocyclylgroups correspond to those listed above in context with substituents onthe cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling.

In these substituents, however, all functional groups have to be lessreactive than the desired reaction sites for the desired reaction,unless a second reaction site is desired, like in the below-describedring formation (ammonia or a primary amine reacts at two reaction sitesof R², thus giving a ring).

Specifically, R³ is H and R⁴ is polycarbocyclyl which may be substitutedas described above. More specifically, R¹ is a 9- to 10-memberedcondensed saturated or partially unsaturated carbocyclic ring system, inparticular selected from indanyl, tetrahydronaphthyl, hexahydronaphthyl,octahydronaphthyl and decahydronaphthyl which may carry one or moresubstituents as defined above. In indanyl and tetrahydronaphthyl theattachment point to N is on the nonaromatic ring moiety. Suitablesubstituents are e.g. selected from the group consisting of halogen,cyano, nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₁-C₄-alkylsubstituted by a radical selected from the group consisting of CN, OH,SH, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, formyl, C₁-C₄-alkylcarbonyl,C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl,amino, C₁-C₄-alkylamino, di-(C₁-C₄-alkyl)amino, phenyl, a 5- or6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4heteroatoms selected from the group consisting of N, O and S as ringmembers and a 9- or 10-membered heteroaromatic bicyclic ring containing1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O andS as ring members, where phenyl and the heteroaromatic rings may carryone or more substituents selected from the group consisting of fluorine,cyano, nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino;

C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, C₁-C₄-alkylcarbonyl,C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl,amino, C₁-C₄-alkylamino, di-(C₁-C₄-alkyl)amino, phenyl, a 5- or6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4heteroatoms selected from the group consisting of N, O and S as ringmembers and a 9- or 10-membered heteroaromatic bicyclic ring containing1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O andS as ring members, where phenyl and the heteroaromatic rings may carryone or more substituents selected from the group consisting of fluorine,cyano, nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino.

R² is specifically alkyl, in particular C₁-C₁₀-alkyl which, apart fromone or more groups LG, may carry other substituents. Suitablesubstituents are those listed above as in context with substituents onthe alkyl groups R¹ and R² in the Suzuki coupling. In particular, thesubstituents are selected from the group consisting of halogen, cyano,nitro, OH, SH, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl,C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members and a 9- or 10-memberedheteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members, wherephenyl and the heteroaromatic rings may carry one or more substituentsselected from the group consisting of fluorine, cyano, nitro, OH, SH,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino. Specifically, the substituents are selected fromthe group consisting of C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl,C₁-C₄-alkoxycarbonyl and C₁-C₄-haloalkoxycarbonyl, and very specificallyfrom C₁-C₄-alkoxycarbonyl and C₁-C₄-haloalkoxycarbonyl.

The reaction product of the amination depends on the substituents R³ andR⁴ and on the molar ratio of the reactants. Thus, if neither R³ nor R⁴is H, the reaction product will generally be a tertiary amineR²—N(R³)R⁴. If R³ is H and R⁴ is not H and R²-LG is used in excess, thereaction product might be a secondary amine R²—N(H)R⁴ or a tertiaryamine (R²)₂NR⁴ or a mixture thereof. If ammonia is used and R²-LG isused in excess, the reaction product might be a primary amine NH₂R², asecondary amine NH(R²)₂ or a tertiary amine (R²)₃N or a mixture thereof.

The reaction product of the amination depends moreover on the nature ofR²: R² may carry more than one leaving group LG, e.g. two. If ammonia ora primary amine is used, this may result in the formation of aheterocyclic ring containing the nitrogen atom deriving from ammonia orthe primary amine as heteroatom ring member, especially if ammonia orthe amine is not used in excess. This ring formation is favoured if thetwo leaving groups are bound at such a distance from each other that a4-, 5-, 6- or 7-membered ring can form. Ring formation is also favouredby a higher dilution of the reactants in the reaction medium.

Amination is generally carried out in the presence of a base. Suitablebases are those listed above in context with the Suzuki reaction, whereespecially inorganic bases, specifically alkali metal hydroxides, suchas NaOH or KOH, are used. In case an organic base is used, this is ofcourse not a primary or secondary amine. The base is generally used inat least equimolar amounts, with respect to that reactant not used inexcess, e.g. in an amount of from 1 to 10 mol per mol of the reactantnot used in excess, in particular 1.5 to 8 mol per mol of the reactantnot used in excess, specifically 2 to 7 mol per mol of the reactant notused in excess. If the reactants are used in equimolar ratio, the aboveamounts of base apply of course to either of the reactants.

Amination is preferably carried out at from 10° C. to 70° C., morepreferably from 20° C. to 70° C., in particular from 30 to 70° C., moreparticularly from 40 to 60° C. and specifically from 45 to 60° C.

The reaction can be carried out by standard proceedings for aminationreactions via nucleophilic substitution, e.g. by mixing all reagents,inclusive base, water and the cellulose derivative, and reacting them atthe desired temperature. Alternatively the reagents can be addedgradually, especially in the case of a continuous or semicontinuousprocess.

Workup proceedings will be described below, as they are similar for mostreactions.

The organic reaction can also take another form of amination than anamination via nucleophilic substitution. For instance, the amination maybe a Michael addition of an N nucleophile.

Michael Addition, Especially of N Nucleophiles

In another particular embodiment of the invention, the organic reactionis a Michael addition, especially of N nucleophiles. In general terms,Michael reaction or Michael addition is the nucleophilic addition of acarbanion or another nucleophile to an α,β-unsaturated carbonylcompound. It belongs to the larger class of conjugate additions. In caseof N nucleophiles, the reaction can be depicted as follows:

R³ and R⁴ are as defined above in context with aminations asnucleophilic substitution. R^(a), R^(b) and R^(c) are independently ofeach other selected from the group consisting of hydrogen, alkyl,alkenyl, alkapolyenyl, alkynyl, alkapolynyl, mixed alkenyl/alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, heterocyclyl, aryl, heteroaryl, or are one of thesubstituents listed in context with the Suzuki reaction as suitableradicals on alkyl, alkenyl, alkapoyenyl, alkynyl, alkapolyynyl or mixedalkenyl/alkynyl groups (however except for oxo (═O), ═S, and ═NR^(12a)).More precisely, R^(a), R^(b) and R^(c) are independently of each otherselected from the group consisting of hydrogen, alkyl, alkenyl,alkapolyenyl, alkynyl, alkapolynyl, mixed alkenyl/alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, nitro,azido, —SCN, —SF₅, OR¹¹, S(O)_(m)R¹¹, NR^(12a)R^(12b), C(═O)R¹³,C(═S)R¹³, C(═NR^(12a))R¹³ or —Si(R¹⁴)₃; where R¹¹, R^(12a), R^(12b),R¹³, R¹⁴ and R¹⁵ are independently as defined above in context with theSuzuki reaction. The alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl,heterocyclyl, aryl, heteroaryl groups can be substituted by one or moresubstituents. Suitable substituents for alkyl, alkenyl, alkapolyenyl,alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl andheteroaryl correspond to those listed above in context with substituentson the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling. Suitable substituents for heterocyclylgroups correspond to those listed above in context with substituents onthe cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling.

In particular at least two of R^(a), R^(b) and R^(c) is hydrogen and theother is alkyl, in particular C₁-C₄-alkyl, which may be substituted. Inparticular, the alkyl substituents are selected from the groupconsisting of halogen, cyano, nitro, OH, SH, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, C₁-C₄-alkylcarbonyl,C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl,amino, C₁-C₄-alkylamino, di-(C₁-C₄-alkyl)amino, phenyl, a 5- or6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4heteroatoms selected from the group consisting of N, O and S as ringmembers and a 9- or 10-membered heteroaromatic bicyclic ring containing1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O andS as ring members, where phenyl and the heteroaromatic rings may carryone or more substituents selected from the group consisting of fluorine,cyano, nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino. Specifically, the substituents are selected fromthe group consisting of OH, C₁-C₆-alkoxy and C₁-C₆-haloalkoxy.

R^(d) is selected from the group consisting of hydrogen, alkyl, alkenyl,alkapolyenyl, alkynyl, alkapolynyl, mixed alkenyl/alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, heterocyclyl, aryl, heteroaryl, OR¹¹, SR¹¹ orNR^(12a)R^(12b); where R¹¹, R^(12a) and R^(12b) are independently asdefined above in context with the Suzuki reaction. The alkyl, alkenyl,alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, heterocyclyl, aryl, heteroaryl groups can besubstituted by one or more substituents. Suitable substituents foralkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroarylcorrespond to those listed above in context with substituents on thealkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling. Suitable substituents for heterocyclylgroups correspond to those listed above in context with substituents onthe cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling.

In particular, R^(d) is selected from the group consisting of OH,C₁-C₆-alkoxy and C₁-C₆-haloalkoxy.

The amine and the α,β-unsaturated carbonyl compound can be used in amolar ratio of from 10:1 to 1:10, e.g. from 5:1 to 1:5 or from 3:1 to1:3 or, preferably, from 2:1 to 1:2.

The reaction is generally carried out in the presence of a base.Suitable bases are those listed above in context with the Suzukireaction. In case an organic base is used, this is of course not aprimary or secondary amine. The base is generally used in at leastequimolar amounts, with respect to that reactant not used in excess,e.g. in an amount of from 1 to 10 mol per mol of the reactant not usedin excess, in particular 1.5 to 8 mol per mol of the reactant not usedin excess, specifically 2 to 7 mol per mol of the reactant not used inexcess. If the reactants are used in equimolar ratio, the above amountsof base apply of course to either of the reactants.

The reaction is preferably carried out at from 10° C. to 60° C., morepreferably from 20° C. to 50° C., in particular from 20 to 40° C., moreparticularly from 20 to 30° C.

The reaction can be carried out by standard proceedings for Michaeladditions, e.g. by mixing all reagents, inclusive base, water and thecellulose derivative, and reacting them at the desired temperature.Alternatively the reagents can be added gradually, especially in thecase of a continuous or semicontinuous process.

Workup proceedings will be described below, as they are similar for mostreactions.

Reductions and Oxidations

In another particular embodiment of the invention, the organic reactionis a reduction or an oxidation reaction, preferably a reductionreaction.

Reduction is the gain of electrons or a decrease in oxidation state by amolecule, atom, or ion. Oxidation, inversely, is the loss of electronsor an increase in oxidation state by a molecule, atom, or ion. Reductionreactions as well as oxidation reactions are of course always redoxreactions, as the reduction agent used in the former case is necessarilyoxidized, and the oxidation agent in the latter case is necessarilyreduced. Redox reactions are however termed “reduction reactions” whenthe product of value is obtained by reducing the respective startingcompound and are analogously termed “oxidation reactions” when theproduct of value is obtained by oxidizing the respective startingcompound.

Reduction Reactions

Reduction reactions are very widespread. Some interesting reductionreactions are for example the reduction of nitro to amino groups, thereduction (hydrogenation) of olefins to alkanes, the reduction of estersto ketones, aldehydes or alcohols, the reduction of ketones or aldehydesto alcohols, the reduction of carbonyl compounds to amines (reductiveamination) or the reduction of nitrile groups to amino groups. Thepresent invention relates in particular to the reduction of nitrocompounds to the corresponding amino compounds, to the reduction of C—Cdouble bonds to C—C single bonds and to reductive aminations.

Reduction of Nitro Compounds

Nitro compounds can be reduced to the corresponding amino compounds byvarious reducing agents, the most widely used methods being thereduction with base metals, usually in acidic solution; and catalytichydrogenation. Also suitable are metal hydrides, such as lithium orsodium hydride, complex hydrides, such as sodium boron hydride (NaBH₄),lithium triethylborohydride (superhydride; LiBH(CH₂CH₃)₂), lithiumtri-sec-butyl(hydrido)borate (L-selectride; LiBH(CH(CH₃)CH₂CH₃)₂),lithium aluminum hydride (LAH; LiAlH₄) or diisobutlyaluminum hydride(DIBAL-H; ((CH₃)₂CHCH₂)₂AlH), or boranes, e.g. diborane.

Base metals which can act as reducing agents are principally all thosewith a suitable redox potential and a reactivity which is controllablein aqueous medium. Despite of their redox potential, alkali metals arethus not very well suited. Examples of suitable base metals are earthalkaline metals, especially magnesium or calcium, aluminum, iron,copper, cobalt, nickel, zinc, titanium or chromium.

In view of their suitable redox potential, controllable reactivity,versatility under various reaction conditions and price, zinc and ironare among the most wide-spread reducing agents. Generally they are usedin an acidic reaction medium, e.g. in diluted aqueous HCl or in ammoniumchloride solution.

Thus, in a particular embodiment, the present invention relates to amethod for reducing nitro compounds with Zn or Fe, optionally in acidicsolution, such as aqueous HCl or ammonium chloride solution. In aspecific embodiment, the present invention relates to a method forreducing nitro compounds with Zn, optionally in acidic solution, such asaqueous HCl or ammonium chloride solution. HCl or ammonium chloride aregenerally used in such concentration/amount that the pH of the reactionmedium is from 1 to 6.

The base metal is generally used in finely divided form, e.g. in form ofsmall granules, powder or dust, and in particular of powder or dust. Asa rule, the less reactive the metal, the finer divided its use form inorder to achieve a sufficient conversion rate. Accordingly, Zn and Feare preferably used in form of powder or dust.

For reduction by catalytic hydrogenation, the catalysts may generally beall prior art catalysts which catalyze the hydrogenation of nitrocompounds to the corresponding amino compounds. The catalysts may beused either in heterogeneous phase or as homogeneous catalysts. Thehydrogenation catalysts preferably comprise at least one metal of groupVIII and also VIIa.

Suitable metals of group VIII are selected from the group consisting ofruthenium, cobalt, rhodium, nickel, palladium und platinum. A suitablemetal of group VIIa is rhenium.

The metals may also be used in the form of mixtures. Metals of groupVIII may also comprise small amounts of further metals, for examplemetals of group VIIa, in particular rhenium, or metals of group Ib, i.e.copper, silver or gold. Particularly suitable metals of group VIII areruthenium, nickel, palladium and platinum. The catalyst especiallycomprises palladium as the catalytically active species.

When a heterogeneous catalyst is used, it is suitably present in finelydivided form. The finely divided form is achieved, for example, asfollows:

a) Black catalyst: shortly before use as a catalyst, the metal isdeposited reductively from the solution of one of its salts.

b) Adams catalyst: the metal oxides, in particular the oxides ofplatinum and palladium, are reduced in situ by the hydrogen used for thehydrogenation.

c) Skeletal or Raney catalyst: the catalyst is prepared as a “metalsponge” from a binary alloy of the metal (in particular nickel orcobalt) with aluminum or silicon by leaching out one partner with acidor alkali. Residues of the original alloy partner often actsynergistically.

d) Supported catalyst: black catalysts can also be precipitated on thesurface of a support substance. Suitable supports and support materialsare described below.

The support material is generally used in the form of a fine powder. Thesupports may consist of metallic or nonmetallic, porous or nonporousmaterial. Suitable metallic materials are, for example, highly alloyedstainless steels. Suitable nonmetallic materials are, for example,mineral materials, for example natural and synthetic minerals, glassesor ceramics, plastics, for example synthetic or natural polymers, or acombination of the two. Preferred support materials are carbon, inparticular activated carbon, silicon dioxide, in particular amorphoussilicon dioxide, alumina, and also the sulfates and carbonates of thealkaline earth metals, calcium carbonate, calcium sulfate, magnesiumcarbonate, magnesium sulfate, barium carbonate and barium sulfate.

The catalyst may be applied to the support by customary processes, forexample by impregnating, wetting or spraying the support with a solutionwhich comprises the catalyst or a suitable precursor thereof.

It is also possible to use homogeneous hydrogenation catalysts, such as,for example, the Wilkinson catalyst and derivatives thereof, orBINAP-ruthenium complexes, e.g. Ru(OAc)₂—(S)-BINAP. However,disadvantages of use of homogeneous catalysts are their preparationcosts and also the fact that they generally cannot be regenerated.Therefore, preference is given to using heterogeneous hydrogenationcatalysts.

The catalytic metal is in particular used in supported form or as metalsponge. Examples of supported catalysts are palladium, nickel orruthenium on carbon, in particular activated carbon, silicon dioxide, inparticular on amorphous silicon dioxide, barium carbonate, calciumcarbonate, magnesium carbonate or alumina.

The metallic catalysts may also be used in the form of their oxides, inparticular palladium oxide, platinum oxide or nickel oxide, which arethen reduced under the hydrogenation conditions to the correspondingmetals.

A suitable metal sponge is for example Raney nickel.

The catalyst and the form in which this is used is selected inaccordance with the type of nitro compound to be reduced. For instance,if the nitro compound contains further functional groups which mayprincipally also be hydrogenated, such as C—C double bonds, aromaticrings, carbonyl, carboxyl or cyano groups, the catalyst and the reactionconditions are chosen to be as selective as possible for the nitrogroup. Suitable conditions and catalysts are known to those skilled inthe art and can be determined by simple preliminary tests.

In a particular embodiment of the present invention, the nitro compoundis an aromatic or heteroaromatic nitro compound R¹—N₂, where R¹ is amono-, bi- or polycyclic aryl or heteroaryl group.

In a particular embodiment the aryl group R¹ is mono-, bi- or tricyclicand is specifically selected from the group consisting of phenyl andnaphthyl; and the heteroaryl group R¹ is in particular mono-, bi- ortricyclic and is specifically selected from the group consisting of 5-or 6-membered heteroaromatic monocyclic rings and 9- or 10-memberedheteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members. Mono-or bicyclic aryl or heteroaryl groups R¹ are for example phenyl,naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl,isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl,[1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls,pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl,isoquinolinyl, quinazalinyl and the like. More particularly, they arefor example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl,1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl,1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl,1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl,1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl,4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl,1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl,1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl,indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromaticbicyclic rings shown below in the “general definitions”. Specifically,R¹ is phenyl.

The aryl and heteroaryl groups R¹ can carry one or more substituents,e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2substituents. Suitable substituents are listed above in context witharyl and heteroaryl groups R¹ and R² in the Suzuki reaction. In aparticular embodiment, the substituents on the aryl and heteroarylgroups R¹ are selected from the group consisting of halogen, cyano,nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl. C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, aminocarbonyl, C₁-C₄-alkylaminocarbonyl,di-(C₁-C₄-alkyl)aminocarbonyl, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members and a 9- or 10-memberedheteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members, wherephenyl and the heteroaromatic rings may carry one or more substituentsselected from the group consisting of halogen, cyano, nitro, OH, SH,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino. The alkyl groups in C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, C₁-C₄-alkylaminocarbonyl anddi-(C₁-C₄-alkyl)aminocarbonyl may in turn carry one or more substituentsselected from the group consisting of halogen, cyano, OH,C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl,C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl,formyl, C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl,C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylaminoand di-(C₁-C₄-alkyl)amino. Specifically, the substituents on the aryland heteroaryl groups R¹ are selected from the group consisting ofhalogen, cyano, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,C₃-C₈-halocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, aminocarbonyl, C₁-C₄-alkylaminocarbonyl anddi-(C₁-C₄-alkyl)aminocarbonyl, where the alkyl groups inC₁-C₄-alkylamino, di-(C₁-C₄-alkyl)amino, C₁-C₄-alkylaminocarbonyl anddi-(C₁-C₄-alkyl)aminocarbonyl may in turn carry one or more substituentsselected from the group consisting of amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino. Specifically, the substituents on the aryl andheteroaryl groups R¹ are selected from the group consisting of halogen,C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, aminocarbonyl, C₁-C₄-alkylaminocarbonyland di-(C₁-C₄-alkyl)aminocarbonyl, where the alkyl groups inC₁-C₄-alkylaminocarbonyl and di-(C₁-C₄-alkyl)aminocarbonyl may in turncarry one or more substituents selected from the group consisting ofamino, C₁-C₄-alkylamino and di-(C₁-C₄-alkyl)amino.

Preferably however, the aryl or heteroaryl groups do not carry anygroups prone to hydrogenation under the applied reaction conditions,such as alkenyl, alkynyl, cycloalkenyl, cycloalkynyl, cyano, C(O)R¹³,C(S)R¹³ or C(═NR^(12a))R¹³ groups.

For such aromatic or heteroaromatic nitro compounds R¹—NO₂, thehydrogenation catalyst is in particular palladium on carbon.

The amount of catalyst to be used depends on factors including theparticular catalytically active metal and its use form, and may bedetermined in the individual case by those skilled in the art. Whennoble metal catalysts are used which comprise, for example, platinum orpalladium, the amount can be smaller by a factor of 10 as compared tothe amount of for example, nickel- or cobalt-containing hydrogenationcatalysts. In case of Pd or Pt, for example, the catalyst is used incatalytic, i.e. substoichiometric amounts, e.g. in an amount of from0.001 to 0.2 mol per mol of nitro compound, in particular 0.005 to 0.1mol per mol of nitro compound, specifically 0.01 to 0.1 mol per mol ofnitro compound. The amount of catalyst specified relates to the amountof active metal, i.e. to the catalytically active component of thecatalyst.

The reduction (with a base metal as well as via hydrogenation) ispreferably carried out at from 10° C. to 60° C., in particular from 20°C. to 55° C., specifically from 20° C. to 50° C. and very specificallyfrom 20° C. to 30° C.

The reaction pressure of the hydrogenation reaction is preferably in therange of from 1 to 250 bar, in particular from 1 to 50 bar and moreparticularly from 1 to 5 bar. In case that the nitro compound containsgroups which can also be hydrogenated, especially aromatic orheteroaromatic rings, it is expedient to work at lower pressure in orderto avoid hydrogenation of such groups. In this case, the reactionpressure of the hydrogenation reaction is preferably in the range from 1to 5 bar, more preferably 1 to 2 bar and in particular 1 to 1.5 bar.

Reduction of C—C Double Bonds

C—C double bonds are generally reduced by hydrogenation. The aboveremarks to the hydrogenation of nitro compounds apply here analogously,except, however, for metal hydrides, complex hydrides and boranes, whichare not suitable here.

Here, too, the catalyst and the form in which this is used is selectedin accordance with the type of olefinically unsaturated compound to bereduced. For instance, if the olefinically unsaturated compound containsfurther functional groups which may principally also be hydrogenated,such as aromatic rings, carbonyl, carboxyl or cyano groups, the catalystand the reaction conditions are chosen to be as selective as possiblefor the C—C double bond. Suitable conditions and catalysts are known tothose skilled in the art and can be determined by simple preliminarytests.

The compound with C—C double bonds to be hydrogenated is preferably anolefinically unsaturated compound, i.e. a compound which contains atleast one C—C double bond which is not part of an aromatic orheteroaromatic system. Preferably it is a compound of formula(R¹)(R²)C═C(R³)(R⁴), where R¹, R², R³, and R⁴, independently of eachother, are hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl,heterocyclyl, aryl, heterocyclyl or are one of the substituents listedin context with the Suzuki as suitable radicals on alkyl, alkenyl,alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl orpolycarbocyclyl groups (however except for oxo (═O), ═S and ═NR^(12a)).More precisely, R¹, R², R³, and R⁴, independently of each other, arehydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl,heterocyclyl, halogen, cyano, nitro, azido, —SCN, —SF₅, OR¹¹,S(O)_(m)R¹¹, NR^(12a)R^(12b), C(═O)R¹³, C(═S)R¹³, C(═NR^(12a))R¹³ or—Si(R¹⁴)₃; where R¹¹, R^(12a), R^(12b), R¹³, R¹⁴ and R¹⁵ areindependently as defined above in context with the Suzuki reaction.

The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl,heteroaryl groups R¹, R², R³ and R⁴ can be substituted by one or moresubstituents. Suitable substituents for alkyl, alkenyl, alkapolyenyl,alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl andheteroaryl correspond to those listed above in context with substituentson the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling. Suitable substituents for heterocyclylgroups correspond to those listed above in context with substituents onthe cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling. Alternatively, R¹ and R³, together withthe carbon atoms they are bound to, form a carbocyclic or heterocyclic,non aromatic ring, where the ring may be substituted; suitablesubstituents corresponding to those listed above in context withsubstituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling.

In particular, R¹, R², R³, and R⁴, independently of each other, arehydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or C(═O)R¹³,where R¹³ is as defined above in context with the Suzuki reaction and isin particular C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy orC₁-C₄-haloalkoxy. Specifically, R¹, R², R³, and R⁴, independently ofeach other, are hydrogen, alkyl, aryl, heteroaryl or C(═O)R¹³, where R¹³is as defined above in context with the Suzuki reaction and is inparticular C₁-C₄-alkyl.

If one or more of R¹, R², R³, and R⁴ are aryl, heteroaryl or C(═O)R¹³,it is expedient to carry out the hydrogenation either under low hydrogenpressure, as said above.

In a specific embodiment, the olefinically unsaturated compound is aMichael-type compound, i.e. a compound carrying an electron withdrawinggroup bound to the C—C double bond, especially a C(O) group, such asC(O)R³. Preferably, one of R¹, R², R³, and R⁴, is C(═O)R¹³, where R¹³ isas defined above in context with the Suzuki reaction and is inparticular C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy orC₁-C₄-haloalkoxy; and the others, independently of each other, arehydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. As said,the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl groups R¹, R², R³and R⁴ can be substituted by one or more substituents. Suitablesubstituents for alkyl, cycloalkyl, aryl and heteroaryl correspond tothose listed above in context with substituents on the alkyl,cycloalkyl, aryl or heteroaryl groups R¹ and R² in the Suzuki coupling.Suitable substituents for heterocyclyl groups correspond to those listedabove in context with substituents on the cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl orheteroaryl groups R¹ and R² in the Suzuki coupling.

In a particular embodiment the reduction agent is ligated CuH. This isgenerally prepared in situ by reacting a Cu salt, generally a Cu(II)salt, e.g. Cu(II) acetate, with a hydride source in the presence of asuitable ligand.

Suitable ligands are those mentioned in context with the Suzuki couplingas Pd or Ni ligands. A specific ligand in this case is6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphine.

Suitable hydride sources are for example silanes, such aspolymethylhydrosiloxane (PMHS; a ca. 29mer), phenylsilane ordiethoxymethylsilane (DEMS). Among these, PMHS is preferred.

If a non-racemic ligand is used and R¹ and R² are different from eachother and are not H and/or R³ and R⁴ are different from each other andare not H, the reduction can proceed stereoselectively and yieldessentially just one stereoisomer.

Suitable non-racemic ligands are for example[(4R)-(4,4′-bis-1,3-benzodioxole)-5,5′-diyl]bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphine]((R)-DTBM-SEGPHOS®), (R)- or (S)-3,5-Xyl-MeO-BIPHEP, (R,S)- or(S,R)-PPF-P(t-Bu)₂, or the Josiphos ligands.

The metal is generally used in catalytic, i.e. substoichiometricamounts, e.g. in an amount of from 0.001 to 0.2 mol per mol of nitrocompound, in particular 0.005 to 0.1 mol per mol of nitro compound,specifically 0.01 to 0.05 mol per mol of olefinically unsaturatedcompound.

The silane is generally used in excess with respect to the compound tobe reduced. “Excess” in this case relates to the amount of hydrogenatoms present in the siloxane molecule, divided by two (as two hydrogenatoms are necessary for the hydrogenation of the double bond), and thus,in case of polymeric silanes, such as PMHS, depends on thepolymerization degree. Generally it used in such an amount that it cantheoretically release 3 to 100 mol of hydrogen atoms per mol of compoundwith C—C double bonds, in particular 3 to 50 mol of hydrogen atoms permol of compound with C—C double bonds, more particularly 4 to 20 mol ofhydrogen atoms per mol of compound with C—C double bonds, specifically 6to 15 mol of hydrogen atoms per mol of compound with C—C double bonds.

The reduction is preferably carried out at from 10° C. to 60° C., inparticular from 20° C. to 55° C., specifically from 20° C. to 50° C. andvery specifically from 20° C. to 30° C.

If the catalyst ligand or any reactant is prone to oxidation by air(such as is the case, for example, for triphenylphosphine,tri(tert-butyl)phosphine, X-Phos,6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphineand several others), the reaction is preferably carried out in an inertatmosphere in order to avoid the presence of oxygen, e.g. under an argonor nitrogen atmosphere. Preferably, moreover, the solvent is used indegassed form. On a laboratory scale this is e.g. obtained by freezing,applying a vacuum and unfreezing under an inert atmosphere or bybubbling a vigorous stream of argon or nitrogen through the solvent orby ultrasonification under an inert atmosphere. On an industrial scaleother methods known in the art can be applied.

Workup proceedings will be described below, as they are similar for mostreactions.

Reductive Amination

In reductive aminations a carbonyl group is converted into an aminogroup via an intermediate imine. The carbonyl group is most commonly aketone or an aldehyde. Generally, the amine first reacts with thecarbonyl group to form a hemiaminal species, which subsequently losesone molecule of water in a reversible manner byalkylimino-de-oxo-bisubstitution, to form the imine. This intermediateimine can then be reduced with a suitable reducing agent to give anamine:

As the reaction is often carried out as a one pot reaction withoutintermediate isolation of the imine, the reduction agent and thereaction conditions are in this case expediently such that the reductionagent does not react with the carbonyl compound before the imine isformed. Suitable reduction agents are complex boron hydrides, such assodium boron hydride (NaBH₄), sodium cyanoborohydride (NaBH₃CN), sodiumtriacetoxyborohydride (NaBH(OCOCH₃)₃), lithium triethylborohydride(superhydride; LiBH(CH₂CH₃)₂), or lithium tri-sec-butyl(hydrido)borate(L-selectride; LiBH(CH(CH₃)CH₂CH₃)₂), or boranes, e.g. diborane orborane complexes, such as borane-2-picoline complex. A specificallysuitable reduction agent is the borane-2-picoline complex. Also suitableis formic acid. In this case, the reductive amination is aLeuckert-Wallach reaction.

R³ and R⁴ are as defined above in context with aminations asnucleophilic substitution. R¹ and R² are independently of each otherselected from the group consisting of hydrogen, alkyl, alkenyl,alkapolyenyl, alkynyl, alkapolynyl, mixed alkenyl/alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, heterocyclyl, aryl, heteroaryl, or are one of thesubstituents listed in context with the Suzuki reaction as suitableradicals on alkyl, alkenyl, alkapoyenyl, alkynyl, alkapolyynyl or mixedalkenyl/alkynyl groups (however except for oxo (═O), ═S, and ═NR^(12a)).More precisely, R¹ and R² are independently of each other selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl,heterocyclyl, aryl, heteroaryl, halogen, cyano, nitro, azido, —SCN,—SF₅, OR¹¹, S(O)_(m)R¹¹, NR^(12a)R^(12b), C(═O)R¹³, C(═S)R¹³,C(═NR^(12a))R¹³ or —Si(R¹⁴)₃; where R¹¹, R^(12a), R^(12b), R¹³, R¹⁴ andR¹⁵ are independently as defined above in context with the Suzukireaction. The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl,heteroaryl groups can be substituted by one or more substituents.Suitable substituents for alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl andheteroaryl correspond to those listed above in context with substituentson the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling. Suitable substituents for heterocyclylgroups correspond to those listed above in context with substituents onthe cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R¹and R² in the Suzuki coupling.

In particular, R³ is H and R⁴ is aryl, where aryl may be substituted asdescribed above. Specifically, R⁴ is phenyl which may be substituted. Inparticular, the aryl or phenyl substituents are selected from the groupconsisting of halogen, cyano, nitro, OH, SH, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, C₁-C₄-alkylcarbonyl,C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkoxycarbonyl,amino, C₁-C₄-alkylamino, di-(C₁-C₄-alkyl)amino, phenyl, a 5- or6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4heteroatoms selected from the group consisting of N, O and S as ringmembers and a 9- or 10-membered heteroaromatic bicyclic ring containing1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O andS as ring members, where phenyl and the heteroaromatic rings may carryone or more substituents selected from the group consisting of fluorine,cyano, nitro, OH, SH, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino anddi-(C₁-C₄-alkyl)amino. Specifically, the substituents are selected fromthe group consisting of OH, C₁-C₆-alkoxy and C₁-C₆-haloalkoxy.

In particular, R¹ is H or C₁-C₄-alkyl and R² is aryl, where aryl may besubstituted as described above. Specifically, R² is phenyl which may besubstituted. In particular, the aryl or phenyl substituents are selectedfrom the group consisting of halogen, cyano, nitro, OH, SH,C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl,C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkoxycarbonyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)amino, phenyl, a 5- or 6-membered heteroaromaticmonocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O and S as ring members and a 9- or 10-memberedheteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatomsselected from the group consisting of N, O and S as ring members, wherephenyl and the heteroaromatic rings may carry one or more substituentsselected from the group consisting of fluorine, cyano, nitro, OH, SH,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, formyl,C₁-C₄-alkylcarbonyl, C₁-C₄-haloalkylcarbonyl, C₁-C₄-alkoxycarbonyl andC₁-C₄-haloalkoxycarbonyl.

The amine and the carbonyl compound can be used in a molar ratio of from5:1 to 1:5, e.g. from 3:1 to 1:3, or from 2:1 to 1:2 or, preferably,from 1.5:1 to 1:1.5.

The reduction agent is generally used in at least equimolar amounts,with respect to that reactant not used in excess, e.g. in an amount offrom 1 to 3 mol per mol of the reactant not used in excess, inparticular 1 to 2 mol per mol of the reactant not used in excess,specifically 1.1 to 1.5 mol per mol of the reactant not used in excess.If the reactants are used in equimolar ratio, the above amounts of baseapply of course to either of the reactants.

The reaction may be carried out in the presence of an acid. Suitableacids are inorganic acids, such as HCl or phosphoric acid, and organicacids, such as acetic acid, trifluoroacetic acid, toluenesulfonic acidor diphenyl phosphate. The acid is generally used in substoichiometricmounts, relative to the reactant not used in excess, such as 1 to 50 mol%, in particular 5 to 20 mol %, relative to 1 mol of that reactant notused in excess.

The reaction is preferably carried out at from 10° C. to 60° C., morepreferably from 20° C. to 50° C., in particular from 20 to 40° C., moreparticularly from 20 to 30° C.

The reaction can be carried out by standard proceedings for reductiveaminations, e.g. by mixing all reagents, inclusive the reduction agent,water and the cellulose derivative, and reacting them at the desiredtemperature. Alternatively the reagents can be added gradually,especially in the case of a continuous or semicontinuous process.

Workup proceedings will be described below, as they are similar for mostreactions.

Although the above reactions have all been depicted as a reactionbetween at least two different molecules, they can of course also becarried out as intramolecular reactions if the reactant contains thesuitable functional groups in a suitable position to each other.Examples are especially intramolecular cyclizations. For instance, acompound containing both an acid and an amino group in a suitabledistance to each other can react in an intramolecular amidation reactionto give a lactam. Suitable dilution is however required forintramolecular reactions if these are not favoured for other reasonsover the respective intermolecular reaction.

The method of the present invention is also suitable for a suit orcascade of reaction steps, which may occur either spontaneously or byaddition of further reagents after completion of one step. For instance,in reactions with Michael-type reactants, like the above-described(Rh-catalyzed) 1,4-additions or the hydrogenation of such compounds, thecarboxyl, ester, amide etc. group may react spontaneously in asubsequent reaction, especially if the Michael-type reactant containsfunctional groups in suitable position which can give a further reactionwith this carboxyl, ester, amide etc. group. For instance, if theMichael-type reactant contains an ester group and also an amine group insuitable position, a lactam can form after or before or during the1,4-addition or the hydrogenation reaction. Another example is theprotection of a functional group in a compound containing more than onefunctional group, e.g. protection of a primary or secondary amino group,of an OH or SH group, reaction of the other functional group(s) in asdesired and deprotection of the protected group and if desired furtherreaction of the deprotected functional group. This suit of reactions canbe carried out as a one pot reaction.

The organic reactions can be carried out in the presence of a surfactant(of course different from the cellulose derivative used according to thepresent invention).

Suitable surfactants are surface-active compounds, such as anionic,cationic, nonionic and amphoteric surfactants, block polymers,polyelectrolytes, and mixtures thereof.

Anionic surfactants are for example alkali, alkaline earth or ammoniumsalts of sulfonates, sulfates, phosphates, carboxylates, and mixturesthereof. Examples of sulfonates are alkylarylsulfonates,diphenylsulfonates, alpha-olefin sulfonates, lignine sulfonates,sulfonates of fatty acids and oils, sulfonates of ethoxylatedalkylphenols, sulfonates of alkoxylated arylphenols, sulfonates ofcondensed naphthalenes, sulfonates of dodecyl- and tridecylbenzenes,sulfonates of naphthalenes and alkylnaphthalenes, sulfosuccinates orsulfosuccinamates. Examples of sulfates are sulfates of fatty acids andoils, of ethoxylated alkylphenols, of alcohols, of ethoxylated alcohols,or of fatty acid esters. Examples of phosphates are phosphate esters.Examples of carboxylates are alkyl carboxylates, and carboxylatedalcohol or alkylphenol ethoxylates.

Nonionic surfactants are for example alkoxylates, N-substituted fattyacid amides, amine oxides, esters, sugar-based surfactants, polymericsurfactants, and mixtures thereof. Examples of alkoxylates are compoundssuch as alcohols, alkylphenols, amines, amides, arylphenols, fatty acidsor fatty acid esters which have been alkoxylated with 1 to 50equivalents. Ethylene oxide and/or propylene oxide may be employed forthe alkoxylation, preferably ethylene oxide. Examples of N-substitutedfatty acid amides are fatty acid glucamides or fatty acid alkanolamides.Examples of esters are fatty acid esters, glycerol esters ormonoglycerides. Examples of sugar-based surfactants are sorbitans,ethoxylated sorbitans, sucrose and glucose esters oralkylpolyglucosides. Examples of polymeric surfactants are home- orcopolymers of vinylpyrrolidone, vinylalcohols, or vinylacetate.

Cationic surfactants are for example quaternary surfactants, for examplequaternary ammonium compounds with one or two hydrophobic groups, orsalts of long-chain primary amines. Suitable amphoteric surfactants arealkylbetains and imidazolines. Suitable block polymers are blockpolymers of the A-B or A-B-A type comprising blocks of polyethyleneoxide and polypropylene oxide, or of the A-B-C type comprising alkanol,polyethylene oxide and polypropylene oxide. Suitable polyelectrolytesare polyacids or polybases. Examples of polyacids are alkali salts ofpolyacrylic acid or polyacid comb polymers. Examples of polybases arepolyvinylamines or polyethyleneamines.

In a particular embodiment, the surfactant is apolyoxyethanyl-α-tocopheryl succinate derivative. Suitable surfactantsof this type are for example the above-described TPGS-750-M, TPGS-1000and PTS-600:

Among these, TPGS-750-M is particularly suitable. Thepolyoxyethanyl-α-tocopheryl succinate derivative surfactants aregenerally used in an amount of from 0.01 to 15% by weight, in particular0.05 to 10% by weight, more particularly 0.1 to 7% by weight,specifically 0.2 to 5% by weight, more specifically 1 to 5% by weight,based on the weight of water (water being the only solvent or making upat least 90% by weight of the solvent, in particular at least 97% byweight of the solvent, the percentages being based on the total weightof the solvent).

Specifically however, no surfactant (different from the cellulosederivative used according to the invention) is used.

One advantage of the method of the present invention is the facileworkup. The cellulose derivative can be removed in a very simple way:after completion of the reaction, the resulting reaction mixture can beextracted with an organic solvent which has a sufficiently lowmiscibility with water and a good solubility for the desired product andreactants, if the conversion was not complete. Suitable organic solventsare for instance alkyl carboxylates, such as ethylacetate, open-chainedethers, such as diethyl ether or methyl-tert-butyl ether, halogenatedalkanes, such as dichloromethane, chloroform or dichloroethane, alkanes,such as pentane, hexane, heptane or technical mixtures like petroleumether, cycloalkanes, like cyclohexane or cycloheptane, or aromaticsolvents, like toluene and the xylenes. In most cases, ethylacetate or aopen-chained ethers, such as diethyl ether or methyl-tert-butyl ether,is the most useful solvent for extraction.

While the desired product and any unreacted reactants move to theorganic phase, the cellulose derivative remains in the aqueous phase. Ifdesired, this aqueous phase can be reused, if necessary after apurification step.

Cellulose derivatives with a viscosity of above 10 mPa·s can be removedby salting them out, i.e. by causing their precipitation by addition ofa salt. For this purpose, an inorganic salt, e.g. in form of an aqueoussolution, is added to the reaction mixture after completion of thereaction, suitably together with an organic solvent as described above.Alternatively, the organic solvent is added first and then the inorganicsalt (solution). Principally, the organic solvent may also be addedafter the inorganic salt (solution). This proceeding is however lesssuited, as the products might precipitate together with the cellulosederivative. The risk of co-precipitation is somewhat reduced forwater-miscible products, as compared to products with low or nowmiscibility with water, but still existent. Suitable salts are forexample sodium sulfate, potassium sulfate, magnesium sulfate, ammoniumsulfate, sodium phosphate, potassium phosphate, sodiumhydrogenphosphate, potassium hydrogenphosphate, sodium chloride and thelike, among which preference is given to salts with large anions, suchas the sulfates, phosphates and hydrogenphosphates. In particular,sodium sulfate is used. The addition of the inorganic salt causes thecellulose derivative to precipitate, which can then be removed bystandard procedures, such as sedimentation, decantation, filtration orcentrifugation, while the product moves to the organic phase. Ifdesired, the aqueous phase can be extracted once or several times withan organic solvent to remove any residual organic products from thewater phase.

Another method for causing precipitation of certain cellulose derivativeis heating, e.g. to at least 80° C.

If desired, the precipitated cellulose derivative can be reactivated andreused in the method of the invention. Reactivation is for exampleachieved by cooling, if precipitation was caused by heating, or bywashing with water to remove the salt with which the cellulosederivative was salted out.

Thus, in a preferred embodiment of the present invention, aftercompletion of the organic reaction the cellulose derivative isprecipitated by heating or by adding an inorganic salt, preferably byadding an inorganic salt, where the inorganic salt is selected from thegroup consisting of sodium sulfate, potassium sulfate, magnesiumsulfate, ammonium sulfate, sodium phosphate, potassium phosphate, sodiumhydrogenphosphate, potassium hydrogenphosphate and sodium chloride, andis in particular sodium sulfate; where precipitation of the cellulosederivative can be carried out before or after removing the reactionproduct and, if present, unreacted starting compounds, and where theprecipitated cellulose derivative, after a reactivation step, can bereused in the method as claimed in any of the preceding claims.

If the organic reaction was carried out in the presence of aheterogenous catalyst, the isolated precipitate (of the precipitatedcellulose derivative) often contains the catalyst in essentiallyquantitative amounts. Thus, not only the cellulose derivative can berecycled, but also the heterogenous catalyst.

If the product is initially obtained as a salt, e.g. because it is aLewis base, e.g. an amine, and the reaction medium is acidic, thereaction mixture is expediently first neutralized or made alkalinebefore the organic solvent is added for extraction, as otherwise theproduct would remain in the aqueous phase. Inversely, if the product isa salt because it is an acid and the reaction medium is basic, thereaction mixture is expediently first neutralized or made acidic beforethe organic solvent is added for extraction, as otherwise the productwould remain in the aqueous phase.

If a silyl compound is used in the reaction, as is the case, forexample, in the CuH reduction of olefinic double bonds with silanes ashydride source, it is expedient to quench this silyl compound, e.g. byaddition of NH₄F.

After separation from the cellulose derivative, the reaction product canbe isolated and, if required, purified by standard procedures, such aschromatographic methods, distillation, sublimation, crystallization etc.

The method of the invention allows carrying out virtually all organicreactions so far carried out in organic solvents. This is surprising incases in which one or more of the reagents or products are not or onlyscarcely water soluble/miscible. This is even more surprising in casesin which one or more of the reagents or products are hydrolyticallylabile or in which water is produced, such as in esterifications or inthe above-described cyclodehydratizations, as one would expect in thelatter case that the reaction would proceed extremely slowly, if at all.

Yields and purities are satisfactory to very good, and, surprisingly, inmany cases better than in organic solvents. The reaction times aregenerally short, especially if higher reaction temperatures, e.g. around50° C., are applied. In some cases, they are even extremely short, suchas just some 15 minutes or even just 10 or 5 or 2 minutes (for a mmolscale).

The cellulose derivatives are significantly less expensive thanTPGS-750-M and the other polyoxyethanyl-α-tocopheryl derivativesdescribed above and readily available. Moreover, they can be easilyseparated from the reaction mixtures. If desired, they can be reused inthe method of the invention, if necessary after a reactivation step.

General Definitions

The organic moieties mentioned in the above definitions of the variablesare—like the term halogen—collective terms for individual listings ofthe individual group members. The prefix C_(n)-C_(m) indicates in eachcase the possible number of carbon atoms in the group.

The term halogen denotes in each case fluorine, bromine, chlorine oriodine.

Pseudohalogens are polyatomic analogues of halogens, whose chemistry,resembling that of the true halogens, allows them to substitute forhalogens in several classes of chemical compounds. Examples forpseudohalogen groups, in terms of the present invention also namedpseudohalogenide groups, pseudohalogenides, pseudohalide groups or orpseudohalides, are —CN, —N₃, —OCN, —NCO, —CNO, —SCN, —NCS or —SeCN.

If the term “alkyl” as used herein and in the alkyl moieties of alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl and the like isused without prefix (C_(n)-C_(m)), it indicates saturated straight-chainor branched aliphatic hydrocarbon radicals having in general 1 to 30(“C₁-C₃₀-alkyl”) carbon atoms, preferably 1 to 20 (“C₁-C₂₀-alkyl”)carbon atoms, in particular 1 to 10 (“C₁-C₃₀-alkyl”) carbon atoms,specifically 1 to 6 (“C₁-C₆-alkyl”) or 1 to 4 (“C₁-C₄-alkyl”) carbonatoms. “C₁-C₂-Alkyl” is a saturated aliphatic hydrocarbon radical having1 or 2 carbon atoms. “C₁-C₃-alkyl” is a saturated straight-chain orbranched aliphatic hydrocarbon radical having 1 to 3 carbon atoms.“C₁-C₄-Alkyl” is a saturated straight-chain or branched aliphatichydrocarbon radical having 1 to 4 carbon atoms. “C₁-C₆-Alkyl” is asaturated straight-chain or branched aliphatic hydrocarbon radicalhaving 1 to 6 carbon atoms. “C₁-C₈-Alkyl” is a saturated straight-chainor branched aliphatic hydrocarbon radical having 1 to 8 carbon atoms;etc. C₁-C₂-Alkyl is methyl or ethyl. Examples for C₁-C₃-alkyl are, inaddition to those mentioned for C₁-C₂-alkyl, propyl and isopropyl.Examples for C₁-C₄-alkyl are, in addition to those mentioned forC₁-C₃-alkyl, butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl(isobutyl) or 1,1-dimethylethyl (tert-butyl). Examples for C₁-C₆-alkylare, in addition to those mentioned for C₁-C₄-alkyl, pentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl,1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl. Examples forC₁-C₈-alkyl are, in addition to those mentioned for C₁-C₆-alkyl, heptyl,octyl, 2-ethylhexyl and positional isomers thereof. Examples forC₁-C₁₀-alkyl are, in addition to those mentioned for C₁-C₆-alkyl, nonyl,decyl and positional isomers thereof. Examples for C₁-C₂₀-alkyl are, inaddition to those mentioned for C₁-C₁₀-alkyl, n-undecyl, n-dodecyl,n-tridecyl, n-tetradecyl, n-hexadecyl, n-heptadecyl, n-octadecyl,n-nonadecyl, n-eicosyl and position isomers thereof. Examples forC₁-C₃₀-alkyl are, in addition to those mentioned for C₁-C₂₀-alkyl,n-henicosyl, n-docosyl, n-tricosyl, n-tetracosyl, n-pentacosyl,n-hexacosyl, n-octacosyl, n-nonacosyl, n-triacontyl and position isomersthereof.

If the term “haloalkyl” as used herein, which is also expressed as“alkyl which is partially or fully halogenated”, and in the alkylmoieties of haloalkoxy, haloalkylthio, haloalkylsulfinyl,haloalkylsulfonyl, haloalkylcarbonyl and the like is used without prefix(C_(n)-C_(m)), it indicates saturated straight-chain or branchedaliphatic hydrocarbon radicals having in general 1 to 30(“C₁-C₃₀-haloalkyl”) carbon atoms, preferably 1 to 20(“C₁-C₂₀-haloalkyl”) carbon atoms, in particular 1 to 10(“C₁-C₁₀-haloalkyl”) carbon atoms, specifically 1 to 6(“C₁-C₆-haloalkyl”) or 1 to 4 (“C₁-C₄-haloalkyl”) carbon atoms, wheresome or all of the hydrogen atoms in these groups are replaced byhalogen atoms as mentioned above, in particular fluorine, chlorineand/or bromine.

“Halomethyl” or “halogenated methyl” or “C₁-haloalkyl” is methyl inwhich 1, 2 or 3 of the hydrogen atoms are replaced by halogen atoms asmentioned above, in particular fluorine, chlorine and/or bromine.“C₁-C₂-Haloalkyl” refers to alkyl groups having 1 or 2 carbon atoms (asmentioned above), where some or all of the hydrogen atoms in thesegroups are replaced by halogen atoms as mentioned above, in particularfluorine, chlorine and/or bromine. “C₁-C₃-Haloalkyl” refers tostraight-chain or branched alkyl groups having 1 to 3 carbon atoms (asmentioned above), where some or all of the hydrogen atoms in thesegroups are replaced by halogen atoms as mentioned above, in particularfluorine, chlorine and/or bromine. “C₁-C₄-Haloalkyl” refers tostraight-chain or branched alkyl groups having 1 to 4 carbon atoms (asmentioned above), where some or all of the hydrogen atoms in thesegroups are replaced by halogen atoms as mentioned above, in particularfluorine, chlorine and/or bromine. “C₁-C₆-Haloalkyl” refers tostraight-chain or branched alkyl groups having 1 to 6 carbon atoms (asmentioned above), where some or all of the hydrogen atoms in thesegroups are replaced by halogen atoms as mentioned above, in particularfluorine, chlorine and/or bromine. “C₁-C₈-Haloalkyl” refers tostraight-chain or branched alkyl groups having 1 to 8 carbon atoms (asmentioned above), where some or all of the hydrogen atoms in thesegroups are replaced by halogen atoms as mentioned above, in particularfluorine, chlorine and/or bromine. “C₁-C₁₀-Haloalkyl” refers tostraight-chain or branched alkyl groups having 1 to 10 carbon atoms (asmentioned above), where some or all of the hydrogen atoms in thesegroups are replaced by halogen atoms as mentioned above, in particularfluorine, chlorine and/or bromine; etc. Examples for halomethyl arebromomethyl, chloromethyl, fluoromethyl, dichloromethyl,trichloromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl,dichlorofluoromethyl, chlorodifluoromethyl and the like. Examples forC₁-C₂-haloalkyl are chloromethyl, bromomethyl, dichloromethyl,trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl,chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl,1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl,2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl,2,2,2-trichloroethyl or pentafluoroethyl. Examples for C₁-C₃-haloalkylare, in addition to those mentioned for C₁-C₂-haloalkyl, 1-fluoropropyl,2-fluoropropyl, 3-fluoropropyl, 1,1-difluoropropyl, 2,2-difluoropropyl,1,2-difluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl,heptafluoropropyl, 1,1,1-trifluoroprop-2-yl, 3-chloropropyl and thelike. Examples for C₁-C₄-haloalkyl are, in addition to those mentionedfor C₁-C₃-haloalkyl, 4-chlorobutyl and the like.

If the term “fluorinated alkyl” is used without prefix (C_(n)-C_(m)), itindicates saturated straight-chain or branched aliphatic hydrocarbonradicals having in general 1 to 30 (“fluorinated C₁-C₃₀-alkyl”) carbonatoms, preferably 1 to 20 (“fluorinated C₁-C₂₀-alkyl”) carbon atoms, inparticular 1 to 10 (“fluorinated C₁-C₁₀-alkyl”) carbon atoms,specifically 1 to 6 (“fluorinated C₁-C₆-alkyl”) or 1 to 4 (“fluorinatedC₁-C₄-alkyl”) carbon atoms, where some or all of the hydrogen atoms inthese groups are replaced by fluorine atoms. “Fluorinated methyl” ismethyl in which 1, 2 or 3 of the hydrogen atoms are replaced by fluorineatoms. “Fluorinated C₁-C₂-alkyl” refers to alkyl groups having 1 or 2carbon atoms (as mentioned above), where some or all of the hydrogenatoms in these groups are replaced by fluorine atoms. “FluorinatedC₁-C₃-alkyl” refers to straight-chain or branched alkyl groups having 1to 3 carbon atoms (as mentioned above), where some or all of thehydrogen atoms in these groups are replaced by fluorine atoms.“Fluorinated C₁-C₄-alkyl” refers to straight-chain or branched alkylgroups having 1 to 4 carbon atoms (as mentioned above), where some orall of the hydrogen atoms in these groups are replaced by fluorineatoms. “Fluorinated C₁-C₆-alkyl” refers to straight-chain or branchedalkyl groups having 1 to 6 carbon atoms (as mentioned above), where someor all of the hydrogen atoms in these groups are replaced by fluorineatoms. “Fluorinated C₁-C₈-alkyl” refers to straight-chain or branchedalkyl groups having 1 to 8 carbon atoms (as mentioned above), where someor all of the hydrogen atoms in these groups are replaced by fluorineatoms. “Fluorinated C₁-C₁₀-alkyl” refers to straight-chain or branchedalkyl groups having 1 to 10 carbon atoms (as mentioned above), wheresome or all of the hydrogen atoms in these groups are replaced byfluorine atoms; etc. Examples for fluorinated methyl are fluoromethyl,difluoromethyl and trifluoromethyl. Examples for fluorinated C₁-C₂-alkylare fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, orpentafluoroethyl. Examples for fluorinated C₁-C₃-alkyl are, in additionto those mentioned for fluorinated C₁-C₂-alkyl, 1-fluoropropyl,2-fluoropropyl, 3-fluoropropyl, 1,1-difluoropropyl, 2,2-difluoropropyl,1,2-difluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl,heptafluoropropyl, 1,1,1-trifluoroprop-2-yl, heptafluoropropyl, and thelike. Examples for fluorinated C₁-C₄-alkyl are, in addition to thosementioned for fluorinated C₁-C₃-alkyl, 4-fluorobutyl, thenonafluorobutyls, the heptadecafluorooctyls and the like.

In perfluorinated alkyl, all hydrogen atoms are replaced by fluorineatoms. Examples are trifluoromethyl, pentafluoroethyl,heptafluoropropyl, the nonafluorobutyls, the heptadecafluorooctyls andthe like.

If the term “hydroxyalkyl” is used without prefix (C_(n)-C_(m)), itindicates saturated straight-chain or branched aliphatic hydrocarbonradicals having in general 1 to 30 (“C₁-C₃₀-hydroxyalkyl”) carbon atoms,preferably 1 to 20 (“C₁-C₂₀-hydroxyalkyl”) carbon atoms, in particular 1to 10 (“C₁-C₁₀-hydroxyalkyl”) carbon atoms, specifically 2 to 6(“C₂-C₆-hydroxyalkyl”) or 2 to 4 (“C₂-C₄-hydroxyalkyl”) or 2 to 3(“C₂-C₃-hydroxyalkyl”) carbon atoms, where one hydrogen atom in thesegroups is replaced by a hydroxyl group. C₂-C₃-Hydroxyalkyl is forexample 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxyprop-1-yl,1-hydroxyprop-2-yl, 2-hydroxyprop-1-yl, 2-hydroxyprop-2-yl or3-hydroxyprop-1-yl, and in particular 2-hydroxyethyl or2-hydroxyprop-1-yl. Examples for C₂-C₄-hydroxyalkyl are, in addition tothose listed for C₂-C₃-hydroxyalkyl, 1-hydroxybut-1-yl,1-hydroxybut-2-yl, 1-hydroxybut-3-yl, 2-hydroxybut-1-yl,2-hydroxybut-2-yl, 2-hydroxybut-3-yl, 3-hydroxybut-1-yl,4-hydroxybut-1-yl, 1-hydroxy-2-methyl-propy-1-yl,2-hydroxy-2-methyl-propy-1-yl, 3-hydroxy-2-methyl-propy-1-yl and2-(hydroxymethyl)-2-methyl-eth-1-yl, and in particular 2-hydroxyethyl,2-hydroxyprop-1-yl or 4-hydroxybut-1-yl.

If the term “alkenyl” as used herein and in the alkyl moieties ofalkenyloxy, alkenylthio, alkenylsulfinyl, alkenylsulfonyl,alkenylcarbonyl and the like is used without prefix (C_(n)-C_(m)), itindicates monounsaturated (i.e. containing one C—C double bond)straight-chain or branched aliphatic hydrocarbon radicals having ingeneral 2 to 30 (“C₂-C₃₀-alkenyl”) carbon atoms, preferably 2 to 20(“C₂-C₂₀-alkenyl”) carbon atoms, in particular 2 to 10(“C₂-C₁₀-alkenyl”) carbon atoms, specifically 2 to 6 (“C₂-C₆-alkenyl”)or 2 to 4 (“C₂-C₄-alkenyl”) carbon atoms, where the C—C double bond canbe in any position. “C₂-C₃-alkenyl” refers to monounsaturatedstraight-chain or branched aliphatic hydrocarbon radicals having 2 to 3carbon atoms and a C—C double bond in any position. “C₂-C₄-alkenyl”refers to monounsaturated straight-chain or branched aliphatichydrocarbon radicals having 2 to 4 carbon atoms and a C—C double bond inany position. “C₂-C₆-alkenyl” refers to monounsaturated straight-chainor branched aliphatic hydrocarbon radicals having 2 to 6 carbon atomsand a C—C double bond in any position. “C₂-C₈-alkenyl” refers tomonounsaturated straight-chain or branched aliphatic hydrocarbonradicals having 2 to 8 carbon atoms and a C—C double bond in anyposition. “C₂-C₁₀-alkenyl” refers to monounsaturated straight-chain orbranched aliphatic hydrocarbon radicals having 2 to 10 carbon atoms anda C—C double bond in any position. Examples for C₂-C₃-alkenyl areethenyl, 1-propenyl, 2-propenyl or 1-methylethenyl. Examples forC₂-C₄-alkenyl are ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl,1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,2-methyl-1-propenyl, 1-methyl-2-propenyl or 2-methyl-2-propenyl.Examples for C₂-C₆-alkenyl are ethenyl, 1-propenyl, 2-propenyl,1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl,2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl,2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl,1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl,1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl,3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl,2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl,1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl,4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl,3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl,1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl,1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl,1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl,2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl,3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl,1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl,2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl,1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl,1-ethyl-2-methyl-2-propenyl and the like. Examples for C₂-C₁₀-alkenylare, in addition to the examples mentioned for C₂-C₆-alkenyl,1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl,4-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 1-decenyl,2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl and the positional isomersthereof.

If the terminal C—C double bond is in a terminal position, i.e. if theradical contains a C═CH₂ group, the alkenyl group is also termed a vinylgroup.

If the term “haloalkenyl” as used herein, which is also expressed as“alkenyl which is partially or fully halogenated”, and in the alkenylmoieties of haloalkenyloxy, haloalkenylthio, haloalkenylsulfinyl,haloalkenylsulfonyl, haloalkenylcarbonyl and the like is used withoutprefix (C_(n)-C_(m)), it indicates monounsaturated straight-chain orbranched aliphatic hydrocarbon radicals having in general 2 to 30(“C₂-C₃₀-haloalkenyl”) carbon atoms, preferably 2 to 20(“C₂-C₂₀-haloalkenyl”) carbon atoms, in particular 2 to 10(“C₂-C₁₀-haloalkenyl”) carbon atoms, specifically 2 to 6(“C₂-C₆-haloalkenyl”) or 2 to 4 (“C₂-C₄-haloalkenyl”) carbon atoms,where some or all of the hydrogen atoms in these groups are replaced byhalogen atoms as mentioned above, in particular fluorine, chlorine andbromine, and where the C—C double bond can be in any position.“C₂-C₃-Haloalkenyl” refers to monounsaturated straight-chain or branchedaliphatic hydrocarbon radicals having 2 to 3 carbon atoms and a C—Cdouble bond in any position (as mentioned above), where some or all ofthe hydrogen atoms in these groups are replaced by halogen atoms asmentioned above, in particular fluorine, chlorine and/or bromine.“C₂-C₄-Haloalkenyl” refers to monounsaturated straight-chain or branchedaliphatic hydrocarbon radicals having 2 to 4 carbon atoms and a C—Cdouble bond in any position (as mentioned above), where some or all ofthe hydrogen atoms in these groups are replaced by halogen atoms asmentioned above, in particular fluorine, chlorine and/or bromine.“C₂-C₆-Haloalkenyl” refers to monounsaturated straight-chain or branchedaliphatic hydrocarbon radicals having 2 to 6 carbon atoms and a doublebond in any position (as mentioned above), where some or all of thehydrogen atoms in these groups are replaced by halogen atoms asmentioned above, in particular fluorine, chlorine and/or bromine.“C₂-C₈-Haloalkenyl” refers to monounsaturated straight-chain or branchedaliphatic hydrocarbon radicals having 2 to 8 carbon atoms and a doublebond in any position (as mentioned above), where some or all of thehydrogen atoms in these groups are replaced by halogen atoms asmentioned above, in particular fluorine, chlorine and/or bromine.“C₂-C₁₀-Haloalkenyl” refers to monounsaturated straight-chain orbranched aliphatic hydrocarbon radicals having 2 to 10 carbon atoms anda double bond in any position (as mentioned above), where some or all ofthe hydrogen atoms in these groups are replaced by halogen atoms asmentioned above, in particular fluorine, chlorine and/or bromine; etc.Examples are chlorovinyl, chloroallyl and the like.

If the term “alkapolyenyl” is used without prefix (C_(n)-C_(m)), itindicates straight-chain or branched aliphatic hydrocarbon radicalshaving in general 4 to 30 (“C₄-C₃₀-alkapolyenyl”) carbon atoms,preferably 4 to 20 (“C₄-C₂₀-alkapolyenyl”) carbon atoms, in particular 4to 10 (“C₄-C₁₀-alkapolyenyl”) carbon atoms, and two or more conjugatedor isolated, but non-cumulated C—C double bonds. Examples arebuta-1,3-dien-1-yl, buta-1,3-dien-2-yl, penta-1,3-dien-1-yl,penta-1,3-dien-2-yl, penta-1,3-dien-3-yl, penta-1,3-dien-4-yl,penta-1,3-dien-5-yl, penta-1,4-dien-1-yl, penta-1,4-dien-2-yl,penta-1,4-dien-3-yl, and the like.

If the term “haloalkapolyenyl” is used without prefix (C_(n)-C_(m)), itindicates straight-chain or branched aliphatic hydrocarbon radicalshaving in general 4 to 30 (“C₄-C₃₀-haloalkapolyenyl”) carbon atoms,preferably 4 to 20 (“C₄-C₂₀-haloalkapolyenyl”) carbon atoms, inparticular 4 to 10 (“C₄-C₁₀-haloalkapolyenyl”) carbon atoms, and two ormore conjugated or isolated, but non-cumulated C—C double bonds, asdefined above, where some or all of the hydrogen atoms in these groupsare replaced by halogen atoms as mentioned above, in particularfluorine, chlorine and bromine.

If the term “alkynyl” as used herein and in the alkynyl moieties ofalkynyloxy, alkynylthio, alkynylsulfinyl, alkynylsulfonyl,alkynylcarbonyl and the like is used without prefix (C_(n)-C_(m)), itindicates straight-chain or branched aliphatic hydrocarbon radicalshaving in general 2 to 30 (“C₂-C₃₀-alkynyl”) carbon atoms, preferably 2to 20 (“C₂-C₂₀-alkynyl”) carbon atoms, in particular 2 to 10(“C₂-C₁₀-alkynyl”) carbon atoms, specifically 2 to 6 (“C₂-C₆-alkynyl”)or 2 to 4 (“C₂-C₄-alkynyl”) carbon atoms, and one triple bond in anyposition. “C₂-C₃-Alkynyl” indicates straight-chain or branchedhydrocarbon radicals having 2 to 3 carbon atoms and one triple bond inany position. “C₂-C₄-Alkynyl” indicates straight-chain or branchedhydrocarbon radicals having 2 to 4 carbon atoms and one triple bond inany position. “C₂-C₆-Alkynyl” indicates straight-chain or branchedhydrocarbon radicals having 2 to 6 carbon atoms and one triple bond inany position. “C₂-C₈-Alkynyl” indicates straight-chain or branchedhydrocarbon radicals having 2 to 8 carbon atoms and one triple bond inany position. “C₂-C₁₀-Alkynyl” indicates straight-chain or branchedhydrocarbon radicals having 2 to 10 carbon atoms and one triple bond inany position; etc. Examples for C₂-C₃-alkynyl are ethynyl, 1-propynyl or2-propynyl. Examples for C₂-C₄-alkynyl are ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl and thelike. Examples for C₂-C₆-alkynyl are ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl,2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl,1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl,1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl,1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl,2-methyl-4-pentynyl, 3-methyl-1-pentynyl, 3-methyl-4-pentynyl,4-methyl-1-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl,1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl,3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl,2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl and the like.

If the term “alkyne” as used herein is used without prefix(C_(n)-C_(m)), it indicates a straight-chain or branched aliphatichydrocarbon having in general 2 to 30 (“C₂-C₃₀-alkyne”) carbon atoms,preferably 2 to 20 (“C₂-C₂₀-alkyne”) carbon atoms, in particular 2 to 10(“C₂-C₁₀-alkyne”) carbon atoms, specifically 2 to 6 (“C₂-C₆-alkyne”) or2 to 4 (“C₂-C₄-alkyne”) carbon atoms, and one triple bond in anyposition. “C₂-C₃-Alkyne” indicates a straight-chain or branchedhydrocarbon having 2 or 3 carbon atoms and one triple bond.“C₂-C₄-Alkyne” indicates a straight-chain or branched hydrocarbon having2 to 4 carbon atoms and one triple bond in any position. “C₂-C₆-Alkyne”indicates a straight-chain or branched hydrocarbon having 2 to 6 carbonatoms and one triple bond in any position. “C₂-C₈-Alkyne” indicates astraight-chain or branched hydrocarbon having 2 to 8 carbon atoms andone triple bond in any position. “C₂-C₁₀-Alkyne” indicates astraight-chain or branched hydrocarbon having 2 to 10 carbon atoms andone triple bond in any position; etc. Examples for C₂-C₃-alkyne areethyne and propyne. Examples for C₂-C₄-alkyne are ethyne, propyne,but-1-yne and but-2-yne. Examples for C₂-C₆-alkynyl are ethyne, propyne,but-1-yne, but-2-yne, pent-1-yne, pent-2-yne, 3-methyl-but-1-yne,hex-1-yne, hex-2-yne, hex-3-yne, 4-methyl-pent-1-yne,4-methyl-pent-2-yne, 3-methyl-pent-1-yne, 3,3-dimethyl-but-1-yne, andthe like.

In a terminal alkyne the C—C triple bond is in a terminal position; i.e.the alkyne contains a C≡CH group.

If the term “haloalkynyl” as used herein, which is also expressed as“alkynyl which is partially or fully halogenated”, and in the alkynylmoieties of haloalkynyloxy, haloalkynylthio, haloalkynylsulfinyl,haloalkynylsulfonyl, haloalkynylcarbonyl and the like is used withoutprefix (C_(n)-C_(m)), it indicates straight-chain or branched aliphatichydrocarbon radicals having in general 2 to 30 (“C₂-C₃₀-haloalkynyl”)carbon atoms, preferably 2 to 20 (“C₂-C₂₀-haloalkynyl”) carbon atoms, inparticular 2 to 10 (“C₂-C₁₀-haloalkynyl”) carbon atoms, specifically 2to 6 (“C₂-C₆-haloalkynyl”) or 2 to 4 (“C₂-C₄-haloalkynyl”) carbon atoms,and one triple bond in any position, where some or all of the hydrogenatoms in these groups are replaced by halogen atoms as mentioned above,in particular fluorine, chlorine and bromine. “C₂-C₃-Haloalkynyl”indicates straight-chain or branched hydrocarbon radicals having 2 to 3carbon atoms and one triple bond in any position, where some or all ofthe hydrogen atoms in these groups are replaced by halogen atoms asmentioned above, in particular fluorine, chlorine and bromine.“C₂-C₄-Haloalkynyl” indicates straight-chain or branched hydrocarbonradicals having 2 to 4 carbon atoms and one triple bond in any position,where some or all of the hydrogen atoms in these groups are replaced byhalogen atoms as mentioned above, in particular fluorine, chlorine andbromine. “C₂-C₆-Haloalkynyl” indicates straight-chain or branchedhydrocarbon radicals having 2 to 6 carbon atoms and one triple bond inany position, where some or all of the hydrogen atoms in these groupsare replaced by halogen atoms as mentioned above, in particularfluorine, chlorine and bromine. “C₂-C₈-Haloalkynyl” indicatesstraight-chain or branched hydrocarbon radicals having 2 to 8 carbonatoms and one triple bond in any position, where some or all of thehydrogen atoms in these groups are replaced by halogen atoms asmentioned above, in particular fluorine, chlorine and bromine.“C₂-C₁₀-Haloalkynyl” indicates straight-chain or branched hydrocarbonradicals having 2 to 10 carbon atoms and one triple bond in anyposition, where some or all of the hydrogen atoms in these groups arereplaced by halogen atoms as mentioned above, in particular fluorine,chlorine and bromine; etc.

If the term “alkapolyynyl” is used without prefix (C_(n)-C_(m)), itindicates straight-chain or branched aliphatic hydrocarbon radicalshaving in general 4 to 30 (“C₄-C₃₀-alkapolyynyl”) carbon atoms,preferably 4 to 20 (“C₄-C₂₀-alkapolyynyl”) carbon atoms, in particular 4to 10 (“C₄-C₁₀-alkypolyenyl”) carbon atoms, and two or more C—C triplebonds. Examples are buta-1,3-diyn-1-yl, penta-1,3-diyn-1-yl,penta-2,4-diyn-1-yl, penta-1,4-diyn-1-yl, penta-1,4-diyn-3-yl, and thelike.

If the term “haloalkapolyynyl” is used without prefix (C_(n)-C_(m)), itindicates straight-chain or branched aliphatic hydrocarbon radicalshaving in general 4 to 30 (“C₄-C₃₀-haloalkapolyynyl”) carbon atoms,preferably 4 to 20 (“C₄-C₂-haloalkapolyynyl”) carbon atoms, inparticular 4 to 10 (“C₄-C₁₀-haloalkapolyynyl”) carbon atoms, and two orC—C double triple, as defined above, where some or all of the hydrogenatoms in these groups are replaced by halogen atoms as mentioned above,in particular fluorine, chlorine and bromine.

“Mixed alkenyl/alkynyl” indicates straight-chain or branched aliphatichydrocarbon radicals having at least one C—C double bond and at leastone C—C triple bond. If the term “mixed alkenyl/alkynyl” is used withoutprefix (C_(n)-C_(m)), it indicates straight-chain or branchedhydrocarbon radicals having in general 4 to 30 (“C₄-C₃₀-mixedalkenyl/alkynyl”) carbon atoms, preferably 4 to 20 (“C₄-C₂₀-mixedalkenyl/alkynyl”) carbon atoms, in particular 4 to 10 (“C₄-C₁₀-mixedalkenyl/alkynyl”) carbon atoms, and at least one C—C double bond and atleast one C—C triple bond.

If the term “mixed haloalkenyl/alkynyl” is used without prefix(C_(n)-C_(m)), it indicates straight-chain or branched aliphatichydrocarbon radicals having in general 4 to 30 (“C₄-C₃₀-mixedhaloalkenyl/alkynyl”) carbon atoms, preferably 4 to 20 (“C₄-C₂₀-mixedhaloalkenyl/alkynyl”) carbon atoms, in particular 4 to 10 (“C₄-C₁₀-mixedhaloalkenyl/alkynyl”) carbon atoms, and at least one C—C double bond andat least one C—C triple bond, where some or all of the hydrogen atoms inthese groups are replaced by halogen atoms as mentioned above, inparticular fluorine, chlorine and bromine.

If the term “cycloalkyl” is used without prefix (C_(n)-C_(m)), itindicates monocyclic saturated hydrocarbon radicals having in general 3to 20 (“C₃-C₂₀-cycloalkyl”), in particular 3 to 10(“C₃-C₁₀-cycloalkyl”), specifically 3 to 8 (“C₃-C₈-cycloalkyl”) or morespecifically 3 to 6 (“C₃-C₆-cycloalkyl”) carbon atoms (and of course noheteroatoms) as ring members; i.e. all ring members are carbon atoms.Examples of cycloalkyl having 3 to 4 carbon atoms comprise cyclopropyland cyclobutyl. Examples of cycloalkyl having 3 to 5 carbon atomscomprise cyclopropyl, cyclobutyl and cyclopentyl. Examples of cycloalkylhaving 3 to 6 carbon atoms comprise cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl. Examples of cycloalkyl having 3 to 8 carbon atomscomprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyland cyclooctyl. Examples of cycloalkyl having 3 to 10 carbon atomscomprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl and cyclodecyl.

If the term “halocycloalkyl”, which is also expressed as “cycloalkylwhich is partially or fully halogenated”, is used without prefix(C_(n)-C_(m)), it indicates monocyclic saturated hydrocarbon radicalshaving in general 3 to 20 (“C₃-C₂₀-halocycloalkyl”), in particular 3 to10 (“C₃-C₁₀-halocycloalkyl”), specifically 3 to 8(“C₃-C₈-halocycloalkyl”) or more specifically 3 to 6(“C₃-C₆-halocycloalkyl”) carbon atoms (as mentioned above), in whichsome or all of the hydrogen atoms are replaced by halogen atoms asmentioned above, in particular fluorine, chlorine and bromine.

If the term “polycarbocyclyl” is used without prefix (C_(n)-C_(m)), itindicates bi- or polycyclic saturated or unsaturated hydrocarbonradicals having in general 4 to 20 (“C₄-C₂₀-polycarbocyclyl”), inparticular 6 to 20 (“C₆-C₂₀-polycarbocyclyl”) carbon atoms (and ofcourse no heteroatoms) as ring members; i.e. all ring members are carbonatoms. The bi- and polycyclic radicals can be condensed, bridged orspiro-bound rings. Unsaturated polycarbocyclyl contains one or more C—Cdouble and/or triple bonds in the ring and are not throughout aromatic.Examples of bicyclic condensed saturated radicals having 6 to 10 carbonatoms comprise bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl,bicyclo[3.3.0]octyl (1,2,3,3a,4,5,6,6a-octahydropentalenyl),bicyclo[4.2.0]octyl, bicyclo[4.3.0]nonyl(2,3,3a,4,5,6,7,7a-octahydro-1H-indene), bicyclo[4.4.0]decyl (decalinyl)and the like. Examples of bridged bicyclic condensed saturated radicalshaving 7 to 10 carbon atoms comprise bicyclo[2.2.1]heptyl,bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and thelike. Examples of bicyclic spiro-bound saturated radicals arespiro[2.2]pentyl, spiro[2.4]heptyl, spiro[4.4]nonyl, spiro[4.5]decyl,spiro[5.5]undecyl and the like. Examples for saturated polycyclicradicals comprise 2,3,4,4a,4b,5,6,7,8,8a,9,9a-dodecahydro-1H-fluorenyl,1,2,3,4,4a,5,6,7,8,8a,9,9a,10,10a-tetradecahydroanthracenyl,1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a-tetradecahydrophenanthrenyl,2,3,3a,4,5,6,6a,7,8,9,9a,9b-dodecahydro-1H-phenalenyl, adamantly and thelike. Examples for bicyclic condensed unsaturated radicals are1,2,3,4,4a,5,8,8a-octahydronaphthalenyl,1,2,3,4,4a,5,6,8a-octahydronaphthalenyl,1,2,3,4,4a,5,6,7-octahydronaphthalenyl,1,2,3,4,5,6,7,8-octahydronaphthalenyl,1,2,3,4,5,8-hexahydronaphthalenyl, 1,4,4a,5,8,8a-hexahydronaphthalenyl,indanyl, indenyl, the hexahydroindenyls, such as2,3,3a,4,7,7a-hexahydro-1H-indenyl or2,3,3a,4,5,7a-hexahydro-1H-indenyl, the tetrahydroindenyls, such as2,3,3a,7a-tetrahydro-1H-indenyl or 2,3,4,7-tetrahydro-1H-indenyl, andthe like. Examples for tricyclic condensed unsaturated radicals arefluorenyl, the dihydrofluorenyl, the tetrahydrofluorenyl, thehexahydrofluorenyls and the decahydrofluorenyls.

Some partially unsaturated polycarbocyclyl rings may be considered asaryl groups in the terms of the present invention if the moiety takingpart in the reaction in question is aromatic. Examples are indanyl,indenyl and fluorenyl: If the reaction takes place on the 6-memberedaromatic moiety of these fused systems or on a functional group bound tothe 6-membered aromatic moiety of these fused systems, the indanyl,indenyl or fluorenyl radical is considered as an aryl ring (see alsobelow definition of aryl). If the reaction is to take place on the5-membered non-aromatic moiety or on a functional group bound to the5-membered non-aromatic moiety, indanyl, indenyl and fluorenyl areconsidered as a polycarbocyclyl ring. Another example is1,2,3,4-tetrahydronaphthyl: If the reaction takes place on the aromaticmoiety of this fused system or on a functional group bound to the6-membered aromatic moiety, the radical is considered as an aryl ring.If it takes place on the non-aromatic moiety or on a functional groupbound thereto, this radical is considered as a polycarbocyclyl ring.

If the term “halopolycarbocyclyl” is used without prefix (C_(n)-C_(m)),it indicates bi- or polycyclic saturated or unsaturated hydrocarbonradicals having in general 4 to 20 (“C₄-C₂₀-halopolycarbocyclyl”), inparticular 6 to 20 (“C₆-C₂₀-halopolycarbocyclyl”) carbon atoms, asdefined above, in which some or all of the hydrogen atoms are replacedby halogen atoms as mentioned above, in particular fluorine, chlorineand bromine. The bi- and polycyclic radicals can be condensed, bridgedor spiro-bound rings.

If the term “cycloalkenyl” is used without prefix (C_(n)-C_(m)), itindicates monocyclic partially unsaturated, non-aromatic hydrocarbonradicals having in general 3 to 20 (“C₃-C₂₀-cycloalkenyl”), inparticular 3 to 10 (“C₃-C₁₀-cycloalkenyl”), specifically 3 to 8(“C₃-C₈-cycloalkenyl”) or more specifically 5 to 7(“C₅-C₇-cycloalkenyl”) carbon atoms (and of course no heteroatoms) asring members; i.e. all ring members are carbon atoms; and one or morenon-cumulative, preferably one, C—C double bonds in the ring. Examplesfor C₅-C₆-cycloalkenyl are cyclopent-1-en-1-yl, cyclopent-1-en-3-yl,cyclopent-1-en-4-yl, cyclopenta-1,3-dien-1-yl, cyclopenta-1,3-dien-2-yl,cyclopenta-1,3-dien-5-yl, cyclohex-1-en-1-yl, cyclohex-1-en-3-yl,cyclohex-1-en-4-yl, cyclohexa-1,3-dien-1-yl, cyclohexa-1,3-dien-2-yl,cyclohexa-1,3-dien-5-yl, cyclohexa-1,4-dien-1-yl andcyclohexa-1,4-dien-3-yl. Examples of C₅-C₇-cycloalkenyl are, in additionto those mentioned above for C₅-C₆-cycloalkenyl, cyclohept-1-en-1-yl,cyclohept-1-en-3-yl, cyclohept-1-en-4-yl, cyclohept-1-en-5-yl,cyclohepta-1,3-dien-1-yl, cyclohepta-1,3-dien-2-yl,cyclohepta-1,3-dien-5-yl, cyclohepta-1,3-dien-6-yl,cyclohepta-1,4-dien-1-yl, cyclohepta-1,4-dien-2-yl,cyclohepta-1,4-dien-3-yl and cyclohepta-1,4-dien-6-yl. Examples ofC₃-C₈-cycloalkenyl are, in addition to those mentioned above forC₅-C₇-cycloalkenyl, cycloprop-1-en-1-yl, cycloprop-1-en-3-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclooct-1-en-1-yl,cyclooct-1-en-3-yl, cyclooct-1-en-4-yl, cyclooct-1-en-5-yl,cycloocta-1,3-dien-1-yl, cycloocta-1,3-dien-2-yl,cycloocta-1,3-dien-5-yl, cycloocta-1,3-dien-6-yl,cycloocta-1,4-dien-1-yl, cycloocta-1,4-dien-2-yl,cycloocta-1,4-dien-3-yl, cycloocta-1,4-dien-6-yl,cycloocta-1,4-dien-7-yl, cycloocta-1,5-dien-1-yl, andcycloocta-1,5-dien-3-yl.

If the term “halocycloalkenyl”, which is also expressed as “cycloalkenylwhich is partially or fully halogenated”, is used without prefix(C_(n)-C_(m)), it indicates monocyclic partially unsaturated,non-aromatic hydrocarbon hydrocarbon radicals having in general 3 to 20(“C₃-C₂₀-halocycloalkenyl”), in particular 3 to 10(“C₃-C₁₀-halocycloalkenyl”), specifically 3 to 8(“C₃-C₈-halocycloalkenyl”) or more specifically 3 to 6(“C₃-C₆-halocycloalkenyl”) carbon atoms (as mentioned above) and one ormore non-cumulative, preferably one, C—C double bonds in the ring, wheresome or all of the hydrogen atoms are replaced by halogen atoms asmentioned above, in particular fluorine, chlorine and bromine.

If the term “cycloalkynyl” is used without prefix (C_(n)-C_(m)), itindicates monocyclic hydrocarbon radicals having in general 8 to 20(“C₈-C₂₀-cycloalkynyl”), in particular 8 to 16 (“C₈-C₁₆-cycloalkynyl”),specifically 8 to 14 (“C₈-C₁₄-cycloalkynyl”) carbon atoms (and of courseno heteroatoms) as ring members; i.e. all ring members are carbon atoms;and one or more, preferably one, C—C triple bonds in the ring. Examplesare cyclooctynyl, cyclodecynyl, cyclododecynyl, cyclotetradecynyl,cyclohexadecynyl and the like.

If the term “halocycloalkynyl”, which is also expressed as “cycloalkynylwhich is partially or fully halogenated”, is used without prefix(C_(n)-C_(m)), it indicates monocyclic hydrocarbon radicals having ingeneral 8 to 20 (“C₈-C₂₀-cycloalkynyl”), in particular 8 to 10(“C₈-C₁₆-cycloalkynyl”), specifically 8 to 14 (“C₈-C₁₄-cycloalkynyl”)carbon atoms and one or more, preferably one, C—C triple bonds in thering, where some or all of the hydrogen atoms are replaced by halogenatoms as mentioned above, in particular fluorine, chlorine and bromine.

“Mixed cycloalkenyl/cycloalkynyl” relates to monocyclic hydrocarbonradicals comprising at least one C—C double bond and at least one C—Ctriple bond in the ring. If used without prefix prefix (C_(n)-C_(m)), itindicates monocyclic hydrocarbon radicals having in general 8 to 20(“C₈-C₂₀-mixed cycloalkenyl/cycloalkynyl”), in particular 8 to 16(“C₈-C₁₆-mixed cycloalkenyl/cycloalkynyl”), specifically 8 to 14(“C₈-C₁₄-mixed cycloalkenyl/cycloalkynyl”) carbon atoms (and of courseno heteroatoms) as ring members; i.e. all ring members are carbon atoms.

If used without prefix prefix (C_(n)-C_(m)), the term “mixedhaloycloalkenyl/cycloalkynyl” indicates monocyclic hydrocarbon radicalshaving in general 8 to 20 (“C₈-C₂₀-mixed cycloalkenyl/cycloalkynyl”), inparticular 8 to 16 (“C₈-C₁₆-mixed cycloalkenyl/cycloalkynyl”),specifically 8 to 14 (“C₈-C₁₄-mixed cycloalkenyl/cycloalkynyl”) carbonatoms and at least one C—C double bond and at least one C—C triple bondin the ring, as defined above, where some or all of the hydrogen atomsare replaced by halogen atoms as mentioned above, in particularfluorine, chlorine and bromine.

If the term “cycloalkyl-alkyl” is used without prefix (C_(n)-C_(m)), itindicates a cycloalkyl group as defined above, in particular aC₃-C₈-cycloalkyl group, specifically a C₃-C₆-cycloalkyl group as definedabove which is bound to the remainder of the molecule via an alkyl groupas defined above, in particular a C₁-C₄-alkyl group. The term“cycloalkyl-C₁-C₄-alkyl” refers to a cycloalkyl group as defined above,in particular a C₃-C₈-cycloalkyl group (“C₃-C₈-cycloalkyl-C₁-C₄-alkyl”),specifically a C₃-C₆-cycloalkyl group (“C₃-C₈-cycloalkyl-C₁-C₄-alkyl”)as defined above, which is bound to the remainder of the molecule via aC₁-C₄-alkyl group, as defined above. Examples forC₃-C₄-cycloalkyl-C₁-C₄-alkyl are cyclopropylmethyl, cyclopropylethyl,cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl andcyclobutylpropyl, Examples for C₃-C₆-cycloalkyl-C₁-C₄-alkyl are, inaddition to those mentioned for C₃-C₄-cycloalkyl-C₁-C₄-alkyl,cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl,cyclohexylmethyl, cyclohexylethyl and cyclohexylpropyl. Examples forC₃-C₈-cycloalkyl-C₁-C₄-alkyl are, in addition to those mentioned forC₃-C₆-cycloalkyl-C₁-C₄-alkyl, cycloheptylmethyl, cycloheptylethyl,cyclooctylmethyl and the like.

If the term “halocycloalkyl-alkyl” is used without prefix (C_(n)-C_(m)),it indicates a halocycloalkyl group as defined above, in particular aC₃-C₈-halocycloalkyl group, specifically a C₃-C₆-halocycloalkyl group asdefined above, which is bound to the remainder of the molecule via analkyl group as defined above, in particular a C₁-C₄-alkyl group. Theterm “halocycloalkyl-C₁-C₄-alkyl” refers to halocycloalkyl group asdefined above, in particular a C₃-C₈-halocycloalkyl group as definedabove, which is bound to the remainder of the molecule via a C₁-C₄-alkylgroup, as defined above.

“Alkoxy” is an alkyl group, as defined above, attached via an oxygenatom to the remainder of the molecule; generally a C₁-C₃₀-alkyl group(“C₁-C₃₀-alkoxy”), preferably a C₁-C₂-alkyl group (“C₁-C₂₀-alkoxy”), inparticular a C₁-C₁₀-alkyl group (“C₁-C₁₀-alkoxy”), specifically aC₁-C₆-alkyl group (“C₁-C₆-alkoxy”) or a C₁-C₄-alkyl group(“C₁-C₄-aloxy”) attached via an oxygen atom to the remainder of themolecule. “C₁-C₂-Alkoxy” is a C₁-C₂-alkyl group, as defined above,attached via an oxygen atom. “C₁-C₃-Alkoxy” is a C₁-C₃-alkyl group, asdefined above, attached via an oxygen atom. C₁-C₂-Alkoxy is methoxy orethoxy. C₁-C₃-Alkoxy is additionally, for example, n-propoxy and1-methylethoxy (isopropoxy). C₁-C₄-Alkoxy is additionally, for example,butoxy, 1-methylpropoxy (sec-butoxy), 2-methylpropoxy (isobutoxy) or1,1-dimethylethoxy (tert-butoxy). C₁-C₆-Alkoxy is additionally, forexample, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy,1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy,1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy,3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy,1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy,2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy,1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxyor 1-ethyl-2-methylpropoxy. C₅-C₈-Alkoxy is additionally, for example,heptyloxy, octyloxy, 2-ethylhexyloxy and positional isomers thereof.C₁-C₁₀-Alkoxy is additionally, for example, nonyloxy, decyloxy andpositional isomers thereof.

“Haloalkoxy” is a haloalkyl group, as defined above, attached via anoxygen atom to the remainder of the molecule; generally aC₁-C₃₀-haloalkyl group (“C₁-C₃₀-haloalkoxy”), preferably aC₁-C₂₀-haloalkyl group (“C₁-C₂₀-haloalkoxy”), in particular aC₁-C₁₀-haloalkyl group (“C₁-C₁₀-haloalkoxy”), specifically aC₁-C₆-haloalkyl group (“C₁-C₆-haloalkoxy”) or a C₁-C₄-haloalkyl group(“C₁-C₄-haloaloxy”) attached via an oxygen atom to the remainder of themolecule. The term “C₁-C₂-haloalkoxy” is a C₁-C₂-haloalkyl group, asdefined above, attached via an oxygen atom. The term “C₁-C₃-haloalkoxy”is a C₁-C₃-haloalkyl group, as defined above, attached via an oxygenatom. C₁-C₂-Haloalkoxy is, for example, OCH₂F, OCHF₂, OCF₃, OCH₂Cl,OCHCl₂, OCCl₃, chlorofluoromethoxy, dichlorofluoromethoxy,chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy,2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy,2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy,2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy or OC₂F₅.C₁-C₃-Haloalkoxy is additionally, for example, 2-fluoropropoxy,3-fluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy,2-chloropropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 2-bromopropoxy,3-bromopropoxy, 3,3,3-trifluoropropoxy, 3,3,3-trichloropropoxy,OCH₂—C₂F₅, OCF₂—C₂F₅, 1-(CH₂F)-2-fluoroethoxy, 1-(CH₂Cl)-2-chloroethoxyor 1-(CH₂Br)-2-bromoethoxy. C₁-C₄-Haloalkoxy is additionally, forexample, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy ornonafluorobutoxy. C₁-C₆-Haloalkoxy is additionally, for example,5-fluoropentoxy, 5-chloropentoxy, 5-bromopentoxy, 5-iodopentoxy,undecafluoropentoxy, 6-fluorohexoxy, 6-chlorohexoxy, 6-bromohexoxy,6-iodohexoxy or dodecafluorohexoxy.

The term “alkoxy-alkyl” as used herein, refers to a straight-chain orbranched alkyl group, as defined above, where one hydrogen atom isreplaced by an alkoxy group, as defined above, generally to aC₁-C₃₀-alkyl group where one hydrogen atom is replaced by aC₁-C₃₀-alkoxy group (“C₁-C₃₀-alkoxy-C₁-C₃₀-alkyl”), preferably to aC₁-C₂₀-alkyl group where one hydrogen atom is replaced by aC₁-C₂₀-alkoxy group (“C₁-C₂₀-alkoxy-C₁-C₂₀-alkyl”), in particular to aC₁-C₁₀-alkyl group where one hydrogen atom is replaced by aC₁-C₁₀-alkoxy group (“C₁-C₁₀-alkoxy-C₁-C₁₀-alkyl”), specifically to aC₁-C₆-alkyl group where one hydrogen atom is replaced by a C₁-C₆-alkoxygroup (“C₁-C₆-alkoxy-C₁-C₆-alkyl”), more specifically to a C₁-C₄-alkylgroup where one hydrogen atom is replaced by a C₁-C₄-alkoxy group(“C₁-C₄-alkoxy-C₁-C₄-alkyl”). The term “C₁-C₃-alkoxy-C₁-C₃-alkyl” asused herein, refers to a straight-chain or branched alkyl group having 1to 3 carbon atoms, as defined above, where one hydrogen atom is replacedby a C₁-C₃-alkoxy group, as defined above. Examples are methoxymethyl,ethoxymethyl, propoxymethyl, isopropoxymethyl, n-butoxymethyl,sec-butoxymethyl, isobutoxymethyl, tert-butoxymethyl, 1-methoxyethyl,1-ethoxyethyl, 1-propoxyethyl, 1-isopropoxyethyl, 1-n-butoxyethyl,1-sec-butoxyethyl, 1-isobutoxyethyl, 1-tert-butoxyethyl, 2-methoxyethyl,2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 2-n-butoxyethyl,2-sec-butoxyethyl, 2-isobutoxyethyl, 2-tert-butoxyethyl,1-methoxypropyl, 1-ethoxypropyl, 1-propoxypropyl, 1-isopropoxypropyl,1-n-butoxypropyl, 1-sec-butoxypropyl, 1-isobutoxypropyl,1-tert-butoxypropyl, 2-methoxypropyl, 2-ethoxypropyl, 2-propoxypropyl,2-isopropoxypropyl, 2-n-butoxypropyl, 2-sec-butoxypropyl,2-isobutoxypropyl, 2-tert-butoxypropyl, 3-methoxypropyl, 3-ethoxypropyl,3-propoxypropyl, 3-isopropoxypropyl, 3-n-butoxypropyl,3-sec-butoxypropyl, 3-isobutoxypropyl, 3-tert-butoxypropyl and the like.

The term “haloalkoxy-alkyl” as used herein, refers to a straight-chainor branched alkyl group, as defined above, where one hydrogen atom isreplaced by an alkoxy group, as defined above, and wherein at least one,e.g. 1, 2, 3, 4 or all of the remaining hydrogen atoms (either in thealkoxy moiety or in the alkyl moiety or in both) are replaced by halogenatoms, in particular by fluorine, chlorine or bromine; generally to aC₁-C₃₀-alkyl group where one hydrogen atom is replaced by aC₁-C₃₀-alkoxy group (“C₁-C₃₀-alkoxy-C₁-C₃₀-alkyl”), preferably to aC₁-C₂₀-alkyl group where one hydrogen atom is replaced by aC₁-C₂₀-alkoxy group (“C₁-C₂₀-alkoxy-C₁-C₂₀-alkyl”), in particular to aC₁-C₁₀-alkyl group where one hydrogen atom is replaced by aC₁-C₁₀-alkoxy group (“C₁-C₁₀-alkoxy-C₁-C₁₀-alkyl”), specifically to aC₁-C₆-alkyl group where one hydrogen atom is replaced by a C₁-C₆-alkoxygroup (“C₁-C₆-alkoxy-C₁-C₆-alkyl”), more specifically to a C₁-C₄-alkylgroup where one hydrogen atom is replaced by a C₁-C₄-alkoxy group(“C₁-C₄-alkoxy-C₁-C₄-alkyl”), and wherein at least one, e.g. 1, 2, 3, 4or all of the remaining hydrogen atoms (either in the alkoxy moiety orin the alkyl moiety or in both) are replaced by halogen atoms, inparticular by fluorine, chlorine or bromine. Examples aredifluoromethoxymethyl (CHF₂OCH₂), trifluoromethoxymethyl,1-difluoromethoxyethyl, 1-trifluoromethoxyethyl, 2-difluoromethoxyethyl,2-trifluoromethoxyethyl, difluoro-methoxy-methyl (CH₃OCF₂),1,1-difluoro-2-methoxyethyl, 2,2-difluoro-2-methoxyethyl and the like.

“Alkylthio” is an alkyl group, as defined above, attached via a sulfuratom to the remainder of the molecule; generally a C₁-C₃₀-alkyl group(“C₁-C₃₀-alkylthio”), preferably a C₁-C₂₀-alkyl group(“C₁-C₂₀-alkylthio”), in particular a C₁-C₁₀-alkyl group(“C₁-C₁₀-alkylthio”), specifically a C₁-C₆-alkyl group(“C₁-C₆-alkylthio”) or a C₁-C₄-alkyl group (“C₁-C₄-alkylthio”) attachedvia a sulfur atom to the remainder of the molecule. The term“C₁-C₂-alkylthio” is a C₁-C₂-alkyl group, as defined above, attached viaa sulfur atom. The term “C₁-C₃-alkylthio” is a C₁-C₃-alkyl group, asdefined above, attached via a sulfur atom. C₁-C₂-Alkylthio is methylthioor ethylthio. C₁-C₃-Alkylthio is additionally, for example, n-propylthioor 1-methylethylthio (isopropylthio). C₁-C₄-Alkylthio is additionally,for example, butylthio, 1-methylpropylthio (sec-butylthio),2-methylpropylthio (isobutylthio) or 1,1-dimethylethylthio(tert-butylthio). C₁-C₆-Alkylthio is additionally, for example,pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio,1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 2,2-dimethylpropylthio,1-ethylpropylthio, hexylthio, 1-methylpentylthio, 2-methylpentylthio,3-methylpentylthio, 4-methylpentylthio, 1,1-dimethylbutylthio,1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,2-dimethylbutylthio,2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio,2-ethylbutylthio, 1,1,2-trimethylpropylthio, 1,2,2-trimethylpropylthio,1-ethyl-1-methylpropylthio or 1-ethyl-2-methylpropylthio.C₁-C₈-Alkylthio is additionally, for example, heptylthio, octylthio,2-ethylhexylthio and positional isomers thereof. C₁-C₁₀-Alkylthio isadditionally, for example, nonylthio, decylthio and positional isomersthereof.

“Haloalkylthio” is a haloalkyl group, as defined above, attached via asulfur atom to the remainder of the molecule; generally aC₁-C₃₀-haloalkyl group (“C₁-C₃₀-haloalkylthio”), preferably aC₁-C₂₀-haloalkyl group (“C₁-C₂₀-haloalkylthio”), in particular aC₁-C₁₀-haloalkyl group (“C₁-C₁₀-haloalkylthio”), specifically aC₁-C₆-haloalkyl group (“C₁-C₆-haloalkylthio”) or a C₁-C₄-haloalkyl group(“C₁-C₄-haloalkylthio”) attached via a sulfur atom to the remainder ofthe molecule. The term “C₁-C₂-haloalkylthio” is a C₁-C₂-haloalkyl group,as defined above, attached via a sulfur atom. The term“C₁-C₃-haloalkylthio” is a C₁-C₃-haloalkyl group, as defined above,attached via a sulfur atom. C₁-C₂-Haloalkylthio is, for example, SCH₂F,SCHF₂, SCF₃, SCH₂Cl, SCHCl₂, SCCl₃, chlorofluoromethylthio,dichlorofluoromethylthio, chlorodifluoromethylthio, 2-fluoroethylthio,2-chloroethylthio, 2-bromoethylthio, 2-iodoethylthio,2,2-difluoroethylthio, 2,2,2-trifluoroethylthio,2-chloro-2-fluoroethylthio, 2-chloro-2,2-difluoroethylthio,2,2-dichloro-2-fluoroethylthio, 2,2,2-trichloroethylthio or SC₂F₅.C₁-C₃-Haloalkylthio is additionally, for example, 2-fluoropropylthio,3-fluoropropylthio, 2,2-difluoropropylthio, 2,3-difluoropropylthio,2-chloropropylthio, 3-chloropropylthio, 2,3-dichloropropylthio,2-bromopropylthio, 3-bromopropylthio, 3,3,3-trifluoropropylthio,3,3,3-trichloropropylthio, SCH₂—C₂F₅, SCF₂—C₂F₅,1-(CH₂F)-2-fluoroethylthio, 1-(CH₂Cl)-2-chloroethylthio or1-(CH₂Br)-2-bromoethylthio. C₁-C₄-Haloalkylthio is additionally, forexample, 4-fluorobutylthio, 4-chlorobutylthio, 4-bromobutylthio ornonafluorobutylthio. C₁-C₆-Haloalkylthio is additionally, for example,5-fluoropentylthio, 5-chloropentylthio, 5-brompentylthio,5-iodopentylthio, undecafluoropentylthio, 6-fluorohexylthio,6-chlorohexylthio, 6-bromohexylthio, 6-iodohexylthio ordodecafluorohexylthio.

“Alkylsulfinyl” is an alkyl group, as defined above, attached via asulfinyl [S(O)] group to the remainder of the molecule; generally aC₁-C₃₀-alkyl group (“C₁-C₃₀-alkylsulfinyl”), preferably a C₁-C₂₀-alkylgroup (“C₁-C₂₀-alkylsulfinyl”), in particular a C₁-C₁₀-alkyl group(“C₁-C₁₀-alkylsulfinyl”), specifically a C₁-C₆-alkyl group(“C₁-C₆-alkylsulfinyl”) or a C₁-C₄-alkyl group (“C₁-C₄-alkylsulfinyl”)attached via a sulfinyl [S(O)] group to the remainder of the molecule.The term “C₁-C₂-alkylsulfinyl” is a C₁-C₂-alkyl group, as defined above,attached via a sulfinyl [S(O)] group. The term “C₁-C₃-alkylsulfinyl” isa C₁-C₃-alkyl group, as defined above, attached via a sulfinyl [S(O)]group. C₁-C₂-Alkylsulfinyl is methylsulfinyl or ethylsulfinyl.C₁-C₄-Alkylsulfinyl is additionally, for example, n-propylsulfinyl,1-methylethylsulfinyl (isopropylsulfinyl), butylsulfinyl,1-methylpropylsulfinyl (sec-butylsulfinyl), 2-methylpropylsulfinyl(isobutylsulfinyl) or 1,1-dimethylethylsulfinyl (tert-butylsulfinyl).C₁-C₆-Alkylsulfinyl is additionally, for example, pentylsulfinyl,1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl,1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl,2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl,1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl,4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl,1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl,2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl,3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl,1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl,1-ethyl-1-methylpropylsulfinyl or 1-ethyl-2-methylpropylsulfinyl.C₁-C₈-Alkylsulfinyl is additionally, for example, heptylsulfinyl,octylsulfinyl, 2-ethylhexylsulfinyl and positional isomers thereof.C₁-C₁₀-Alkylsulfinyl is additionally, for example, nonylsulfinyl,decylsulfinyl and positional isomers thereof.

“Haloalkylsulfinyl” is a haloalkyl group, as defined above, attached viaa sulfinyl [S(O)] group to the remainder of the molecule; generally aC₁-C₃₀-haloalkyl group (“C₁-C₃₀-haloalkylsulfinyl”), preferably aC₁-C₂₀-haloalkyl group (“C₁-C₂₀-haloalkylsulfinyl”), in particular aC₁-C₁₀-haloalkyl group (“C₁-C₁₀-haloalkylsulfinyl”), specifically aC₁-C₆-haloalkyl group (“C₁-C₆-haloalkylsulfinyl”) or a C₁-C₄-haloalkylgroup (“C₁-C₄-haloalkylsulfinyl”) attached via a sulfinyl [S(O)] groupto the remainder of the molecule. The term “C₁-C₂-haloalkylsulfinyl” isa C₁-C₂-haloalkyl group, as defined above, attached via a sulfinyl[S(O)] group. The term “C₁-C₃-haloalkylsulfinyl” is a C₁-C₃-haloalkylgroup, as defined above, attached via a sulfinyl [S(O)] group.C₁-C₂-Haloalkylsulfinyl is, for example, S(O)CH₂F, S(O)CHF₂, S(O)CF₃,S(O)CH₂Cl, S(O)CHCl₂, S(O)CCl₃, chlorofluoromethylsulfinyl,dichlorofluoromethylsulfinyl, chlorodifluoromethylsulfinyl,2-fluoroethylsulfinyl, 2-chloroethylsulfinyl, 2-bromoethylsulfinyl,2-iodoethylsulfinyl, 2,2-difluoroethylsulfinyl,2,2,2-trifluoroethylsulfinyl, 2-chloro-2-fluoroethylsulfinyl,2-chloro-2,2-difluoroethylsulfinyl, 2,2-dichloro-2-fluoroethylsulfinyl,2,2,2-trichloroethylsulfinyl or S(O)C₂F₅. C₁-C₄-Haloalkylsulfinyl isadditionally, for example, 2-fluoropropylsulfinyl,3-fluoropropylsulfinyl, 2,2-difluoropropylsulfinyl,2,3-difluoropropylsulfinyl, 2-chloropropylsulfinyl,3-chloropropylsulfinyl, 2,3-dichloropropylsulfinyl,2-bromopropylsulfinyl, 3-bromopropylsulfinyl,3,3,3-trifluoropropylsulfinyl, 3,3,3-trichloropropylsulfinyl,S(O)CH₂—C₂F₅, S(O)CF₂—C₂F₅, 1-(CH₂F)-2-fluoroethylsulfinyl,1-(CH₂Cl)-2-chloroethylsulfinyl, 1-(CH₂Br)-2-bromoethylsulfinyl,4-fluorobutylsulfinyl, 4-chlorobutylsulfinyl, 4-bromobutylsulfinyl ornonafluorobutylsulfinyl. C₁-C₆-Haloalkylsulfinyl is additionally, forexample, 5-fluoropentylsulfinyl, 5-chloropentylsulfinyl,5-brompentylsulfinyl, 5-iodopentylsulfinyl, undecafluoropentylsulfinyl,6-fluorohexylsulfinyl, 6-chlorohexylsulfinyl, 6-bromohexylsulfinyl,6-iodohexylsulfinyl or dodecafluorohexylsulfinyl.

“Alkylsulfonyl” is an alkyl group, as defined above, attached via asulfonyl [S(O)₂] group to the remainder of the molecule; generally aC₁-C₃₀-alkyl group (“C₁-C₃₀-alkylsulfonyl”), preferably a C₁-C₂₀-alkylgroup (“C₁-C₂₀-alkylsulfonyl”), in particular a C₁-C₁₀-alkyl group(“C₁-C₁₀-alkylsulfonyl”), specifically a C₁-C₆-alkyl group(“C₁-C₆-alkylsulfonyl”) or a C₁-C₄-alkyl group (“C₁-C₄-alkylsulfonyl”)attached via a sulfonyl [S(O)₂] group to the remainder of the molecule.The term “C₁-C₂-alkylsulfonyl” is a C₁-C₂-alkyl group, as defined above,attached via a sulfonyl [S(O)₂] group. The term “C₁-C₃-alkylsulfonyl” isa C₁-C₃-alkyl group, as defined above, attached via a sulfonyl [S(O)₂]group. C₁-C₂-Alkylsulfonyl is methylsulfonyl or ethylsulfonyl.C₁-C₃-Alkylsulfonyl is additionally, for example, n-propylsulfonyl or1-methylethylsulfonyl (isopropylsulfonyl). C₁-C₄-Alkylsulfonyl isadditionally, for example, butylsulfonyl, 1-methylpropylsulfonyl(sec-butylsulfonyl), 2-methylpropylsulfonyl (isobutylsulfonyl) or1,1-dimethylethylsulfonyl (tert-butylsulfonyl). C₁-C₆-Alkylsulfonyl isadditionally, for example, pentylsulfonyl, 1-methylbutylsulfonyl,2-methylbutylsulfonyl, 3-methylbutylsulfonyl,1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl,2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl,1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl,4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl,1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl,2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl,3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl,1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl,1-ethyl-1-methylpropylsulfonyl or 1-ethyl-2-methylpropylsulfonyl.C₁-C₈-Alkylsulfonyl is additionally, for example, heptylsulfonyl,octylsulfonyl, 2-ethylhexylsulfonyl and positional isomers thereof.C₁-C₁₀-Alkylsulfonyl is additionally, for example, nonylsulfonyl,decylsulfonyl and positional isomers thereof.

“Haloalkylsulfonyl” is a haloalkyl group, as defined above, attached viaa sulfonyl [S(O)₂] group to the remainder of the molecule; generally aC₁-C₃₀-haloalkyl group (“C₁-C₃₀-haloalkylsulfonyl”), preferably aC₁-C₂₀-haloalkyl group (“C₁-C₂₀-haloalkylsulfonyl”), in particular aC₁-C₁₀-haloalkyl group (“C₁-C₁₀-haloalkylsulfonyl”), specifically aC₁-C₆-haloalkyl group (“C₁-C₆-haloalkylsulfonyl”) or a C₁-C₄-haloalkylgroup (“C₁-C₄-haloalkylsulfonyl”) attached via a sulfonyl [S(O)₂] groupto the remainder of the molecule. The term “C₁-C₂-haloalkylsulfonyl” isa C₁-C₂-haloalkyl group, as defined above, attached via a sulfonyl[S(O)₂] group. The term “C₁-C₃-haloalkylsulfonyl” is a C₁-C₃-haloalkylgroup, as defined above, attached via a sulfonyl [S(O)₂] group.C₁-C₂-Haloalkylsulfonyl is, for example, S(O)CH₂F, S(O)₂CHF₂, S(OCF₃,S(O)₂CH₂Cl, S(O)₂CHCl₂, S(O)₂CCl₃, chlorofluoromethylsulfonyl,dichlorofluoromethylsulfonyl, chlorodifluoromethylsulfonyl,2-fluoroethylsulfonyl, 2-chloroethylsulfonyl, 2-bromoethylsulfonyl,2-iodoethylsulfonyl, 2,2-difluoroethylsulfonyl,2,2,2-trifluoroethylsulfonyl, 2-chloro-2-fluoroethylsulfonyl,2-chloro-2,2-difluoroethylsulfonyl, 2,2-dichloro-2-fluoroethylsulfonyl,2,2,2-trichloroethylsulfonyl or S(O)₂C₂F₅. C₁-C₃-Haloalkylsulfonyl isadditionally, for example, 2-fluoropropylsulfonyl,3-fluoropropylsulfonyl, 2,2-difluoropropylsulfonyl,2,3-difluoropropylsulfonyl, 2-chloropropylsulfonyl,3-chloropropylsulfonyl, 2,3-dichloropropylsulfonyl,2-bromopropylsulfonyl, 3-bromopropylsulfonyl,3,3,3-trifluoropropylsulfonyl, 3,3,3-trichloropropylsulfonyl,S(O)₂CH₂—C₂F₅, S(O)₂CF₂—C₂F₅, 1-(CH₂F)-2-fluoroethylsulfonyl,1-(CH₂Cl)-2-chloroethylsulfonyl or 1-(CH₂Br)-2-bromoethylsulfonyl.C₁-C₄-Haloalkylsulfonyl is additionally, for example,4-fluorobutylsulfonyl, 4-chlorobutylsulfonyl, 4-bromobutylsulfonyl ornonafluorobutylsulfonyl. C₁-C₄-Haloalkylsulfonyl is additionally, forexample, 5-fluoropentylsulfonyl, 5-chloropentylsulfonyl,5-brompentylsulfonyl, 5-iodopentylsulfonyl, undecafluoropentylsulfonyl,6-fluorohexylsulfonyl, 6-chlorohexylsulfonyl, 6-bromohexylsulfonyl,6-iodohexylsulfonyl or dodecafluorohexylsulfonyl.

The substituent “oxo” replaces a CH₂ group by a C(═O) group.

Alike, the substituent “═S” replaces a CH₂ group by a C(═S) group.

Alike, the substituent “═NR^(12a)” replaces a CH₂ group by aC(═NR^(12a)) group.

“Alkylcarbonyl” is an alkyl group, as defined above, attached via acarbonyl [C(═O)] group to the remainder of the molecule; generally aC₁-C₃₀-alkyl group (“C₁-C₃₀-alkylcarbonyl”), preferably a C₁-C₂₀-alkylgroup (“C₁-C₂₀-alkylcarbonyl”), in particular a C₁-C₁₀-alkyl group(“C₁-C₁₀-alkylcarbonyl”), specifically a C₁-C₆-alkyl group(“C₁-C₆-alkylcarbonyl”) or a C₁-C₄-alkyl group (“C₁-C₄-alkylcarbonyl”)attached via a carbonyl [C(═O)] group to the remainder of the molecule.Examples are acetyl (methylcarbonyl), propionyl (ethylcarbonyl),propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl and the like.

“Haloalkylcarbonyl” is a haloalkyl group, as defined above, attached viaa carbonyl [C(═O)] group to the remainder of the molecule; generally aC₁-C₃₀-haloalkyl group (“C₁-C₃₀-haloalkylcarbonyl”), preferably aC₁-C₂₀-haloalkyl group (“C₁-C₂₀-haloalkylcarbonyl”), in particular aC₁-C₁₀-haloalkyl group (“C₁-C₁₀-haloalkylcarbonyl”), specifically aC₁-C₆-haloalkyl group (“C₁-C₆-haloalkylcarbonyl”) or a C₁-C₄-haloalkylgroup (“C₁-C₄-haloalkylcarbonyl”) attached via a carbonyl [C(═O)] groupto the remainder of the molecule. Examples are trifluoromethylcarbonyl,2,2,2-trifluoroethylcarbonyl and the like.

“Alkoxycarbonyl” is an alkoxy group, as defined above, attached via acarbonyl [C(═O)] group to the remainder of the molecule; generally aC₁-C₃-alkoxy group (“C₁-C₃₀-alkoxycarbonyl”), preferably a C₁-C₂₀-alkoxygroup (“C₁-C₂₀-alkoxycarbonyl”), in particular a C₁-C₁₀-alkoxy group(“C₁-C₁₀-alkoxycarbonyl”), specifically a C₁-C₆-alkoxy group(“C₁-C₆-alkoxycarbonyl”) or a C₁-C₄-alkoxy group(“C₁-C₄-alkoxycarbonyl”) attached via a carbonyl [C(═O)] group to theremainder of the molecule. Examples are methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl and the like.

“Haloalkoxycarbonyl” is a haloalkoxy group, as defined above, attachedvia a carbonyl [C(═O)] group to the remainder of the molecule; generallya C₁-C₃₀-haloalkoxy group (“C₁-C₃₀-haloalkoxycarbonyl”), preferably aC₁-C₂₀-haloalkoxy group (“C₁-C₂₀-haloalkoxycarbonyl”), in particular aC₁-C₁₀-haloalkoxy group (“C₁-C₁₀-haloalkoxycarbonyl”), specifically aC₁-C₆-haloalkoxy group (“C₁-C₆-haloalkoxycarbonyl”) or aC₁-C₄-haloalkoxy group (“C₁-C₄-haloalkoxycarbonyl”) attached via acarbonyl [C(═O)] group to the remainder of the molecule. Examples aretrifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl and the like.

The term “aminocarbonyl” is a group —C(═O)—NH₂.

The term “alkylaminocarbonyl” is a group —C(═O)—N(H)-alkyl, where alkylis as defined above and is in general a C₁-C₃₀-alkyl group(“C₁-C₃₀-alkylaminocarbonyl”), preferably a C₁-C₂₀-alkyl group(“C₁-C₂₀-alkylaminocarbonyl”), in particular a C₁-C₁₀-alkyl group(“C₁-C₁₀-alkylaminocarbonyl”), specifically a C₁-C₆-alkyl group(“C₁-C₆-alkylaminocarbonyl”) or a C₁-C₄-alkyl group(“C₁-C₄-alkylaminocarbonyl”). Examples are methylaminocarbonyl,ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl,butylaminocarbonyl and the like.

The term “di(alkyl)aminocarbonyl” is a group —C(═O)—N(alkyl)₂, whereeach alkyl is independently as defined above and is independently ingeneral a C₁-C₆-alkyl group (“di-(C₁-C₃₀-alkyl)aminocarbonyl”),preferably a C₁-C₂₀-alkyl group (“di-(C₁-C₂₀-alkyl)aminocarbonyl”), inparticular a C₁-C₁₀-alkyl group (“di-(C₁-C₁₀-alkyl)aminocarbonyl”),specifically a C₁-C₆-alkyl group (“di-(C₁-C₆-alkyl)aminocarbonyl”), or aC₁-C₄-alkyl group (“di-(C₁-C₄-alkyl)aminocarbonyl”). Examples aredimethylaminocarbonyl, diethylaminocarbonyl, ethylmethylaminocarbonyl,dipropylaminocarbonyl, diisopropylaminocarbonyl,methylpropylaminocarbonyl, methylisopropylaminocarbonyl,ethylpropylaminocarbonyl, ethylisopropylaminocarbonyl,dibutylaminocarbonyl and the like.

Aryl is a mono-, bi- or polycyclic carbocyclic (i.e. without heteroatomsas ring members) aromatic radical. One example for a monocyclic aromaticradical is phenyl. In bicyclic aryl rings two aromatic rings arecondensed, i.e. they share two vicinal C atoms as ring members. Oneexample for a bicyclic aromatic radical is naphthyl. In polycyclic arylrings, three or more rings are condensed. Examples for polycyclic arylradicals are phenanthrenyl, anthracenyl, tetracenyl,1H-benzo[a]phenalenyl, pyrenyl and the like. In the terms of the presentinvention “aryl” encompasses however also bi- or polycyclic radicals inwhich not all rings are aromatic, as long as at least one ring is;especially if the reactive site is on the aromatic ring (or on afunctional group bound thereto). Examples are indanyl, indenyl,tetralinyl, 6,7,8,9-tetrahydro-5H-benzo[7]annulenyl, fluorenyl,9,10-dihydroanthracenyl, 9,10-dihydrophenanthrenyl,1H-benzo[a]phenalenyl and the like, and also ring systems in which notall rings are condensed, but for example spiro-bound or bridged, such asbenzonorbornyl. In particular, the aryl group has 6 to 30, moreparticularly 6 to 20, specifically 6 to 10 carbon atoms as ring members.

Rings termed as heterocyclic rings or heterocyclyl or heteroaromaticrings or heteroaryl or hetaryl contain one or more heteroatoms as ringmembers, i.e. atoms different from carbon. In the terms of the presentinvention, these heteroatoms are N, O and S, where N and S can also bepresent as heteroatom groups, namely as NO, SO or SO₂. Thus, in theterms of the present invention, rings termed as heterocyclic rings orheterocyclyl or heteroaromatic rings or heteroaryl or hetaryl containone or more heteroatoms and/or heteroatom groups selected from the groupconsisting of N, O, S, NO, SO and SO₂ as ring members.

In the terms of the present invention a heterocyclic ring orheterocyclyl is a saturated, partially unsaturated or maximallyunsaturated, but not aromatic heteromono-, bi- or polycyclic ring (ifthe ring is aromatic, it is termed heteroaromatic ring or heteroaryl orhetaryl) containing one ore more, in particular 1, 2, 3 or 4 heteroatomsor heteroatom groups independently selected from the group consisting ofN, O, S, NO, SO and SO₂ as ring members.

Unsaturated rings contain at least one C—C and/or C—N and/or N—N doublebond(s). Maximally unsaturated rings contain as many conjugated C—Cand/or C—N and/or N—N double bonds as allowed by the ring size.Maximally unsaturated 5- or 6-membered heteromonocyclic rings aregenerally aromatic (and thus not enclosed in the present term“heterocyclic ring” or “heterocyclyl”. Exceptions are maximallyunsaturated 6-membered rings containing O, S, SO and/or SO₂ as ringmembers, such as pyran and thiopyran, which are not aromatic). Partiallyunsaturated rings contain less than the maximum number of C—C and/or C—Nand/or N—N double bond(s) allowed by the ring size.

Although they do not contain as many conjugated double bonds asprincipally allowed by the ring size, some partially unsaturatedheterobi- or polycyclic rings may be considered as heteroaromatic in theterms of the present invention if the moiety taking part in the reactionin question is aromatic. One example is indoline: If the reaction takesplace on the 6-membered aromatic moiety of this fused system, theindoline is considered as a heteroaromatic ring. See also below examplesfor partially unsaturated heterobicyclic rings. If the reaction is totake place on the 5-membered non-aromatic moiety, indoline is consideredas a heterocyclyl ring.

The heterocyclic and heteroaromatic ring may be attached to theremainder of the molecule via a carbon ring member or via a nitrogenring member. As a matter of course, the heterocyclic and heteroaromaticring contains at least one carbon ring atom. If the ring contains morethan one O ring atom, these are not adjacent.

Heterocyclic rings are in particular 3 to 30-membered, more particularly3 to 20-membered, specifically 3- to 12-membered or 3- to 11-membered.

Heteromonocyclic rings are in particular 3- to 8-membered. The term “3-,4-, 5-, 6-, 7- or 8-membered heterocyclic ring containing 1, 2, 3 or 4heteroatoms or heteroatom groups independently selected from the groupconsisting of N, O, S, NO, SO and SO₂ groups as ring members” denotes a3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated ormaximum unsaturated (but not aromatic) heteromonocyclic ring containing1, 2, 3 or 4 (preferably 1, 2 or 3) heteroatoms or heteroatom groupsselected from the group consisting of N, O, S, SO and SO₂ as ringmembers.

Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered saturatedheteromonocyclic ring include: Oxiran-2-yl, thiiran-2-yl, aziridin-1-yl,aziridin-2-yl, oxetan-2-yl, oxetan-3-yl, thietan-2-yl, thietan-3-yl,1-oxothietan-2-yl, 1-oxothietan-3-yl, 1,1-dioxothietan-2-yl,1,1-dioxothietan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl,tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,tetrahydrothien-3-yl, 1-oxotetrahydrothien-2-yl,1,1-dioxotetrahydrothien-2-yl, 1-oxotetrahydrothien-3-yl,1,1-dioxotetrahydrothien-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,pyrrolidin-3-yl, pyrazolidin-1-yl, pyrazolidin-3-yl, pyrazolidin-4-yl,pyrazolidin-5-yl, imidazolidin-1-yl, imidazolidin-2-yl,imidazolidin-4-yl, oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl,oxazolidin-5-yl, isoxazolidin-2-yl, isoxazolidin-3-yl,isoxazolidin-4-yl, isoxazolidin-5-yl, thiazolidin-2-yl,thiazolidin-3-yl, thiazolidin-4-yl, thiazolidin-5-yl,isothiazolidin-2-yl, isothiazolidin-3-yl, isothiazolidin-4-yl,isothiazolidin-5-yl, 1,2,4-oxadiazolidin-2-yl, 1,2,4-oxadiazolidin-3-yl,1,2,4-oxadiazolidin-4-yl, 1,2,4-oxadiazolidin-5-yl,1,2,4-thiadiazolidin-2-yl, 1,2,4-thiadiazolidin-3-yl,1,2,4-thiadiazolidin-4-yl, 1,2,4-thiadiazolidin-5-yl,1,2,4-triazolidin-1-yl, 1,2,4-triazolidin-3-yl, 1,2,4-triazolidin-4-yl,1,3,4-oxadiazolidin-2-yl, 1,3,4-oxadiazolidin-3-yl,1,3,4-thiadiazolidin-2-yl, 1,3,4-thiadiazolidin-3-yl,1,3,4-triazolidin-1-yl, 1,3,4-triazolidin-2-yl, 1,3,4-triazolidin-3-yl,tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl, 1,4-dioxan-2-yl,piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,hexahydropyridazin-1-yl, hexahydropyridazin-3-yl,hexahydropyridazin-4-yl, hexahydropyrimidin-1-yl,hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl,hexahydropyrimidin-5-yl, piperazin-1-yl, piperazin-2-yl,1,3,5-hexahydrotriazin-1-yl, 1,3,5-hexahydrotriazin-2-yl,1,2,4-hexahydrotriazin-1-yl, 1,2,4-hexahydrotriazin-2-yl,1,2,4-hexahydrotriazin-3-yl, 1,2,4-hexahydrotriazin-4-yl,1,2,4-hexahydrotriazin-5-yl, 1,2,4-hexahydrotriazin-6-yl,morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, thiomorpholin-2-yl,thiomorpholin-3-yl, thiomorpholin-4-yl, 1-oxothiomorpholin-2-yl,1-oxothiomorpholin-3-yl, 1-oxothiomorpholin-4-yl,1,1-dioxothiomorpholin-2-yl, 1,1-dioxothiomorpholin-3-yl,1,1-dioxothiomorpholin-4-yl, azepan-1-, -2-, -3- or -4-yl, oxepan-2-,-3-, -4- or -5-yl, hexahydro-1,3-diazepinyl, hexahydro-1,4-diazepinyl,hexahydro-1,3-oxazepinyl, hexahydro-1,4-oxazepinyl,hexahydro-1,3-dioxepinyl, hexahydro-1,4-dioxepinyl,

oxocane, thiocane, azocanyl, [1,3]diazocanyl, [1,4]diazocanyl,[1,5]diazocanyl, [1,5]oxazocanyl and the like.

Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered partially unsaturatedheteromonocyclic ring include: 2,3-dihydrofuran-2-yl,2,3-dihydrofuran-3-yl, 2,4-dihydrofuran-2-yl, 2,4-dihydrofuran-3-yl,2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl, 2,4-dihydrothien-2-yl,2,4-dihydrothien-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl,3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl,4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl,4-isoxazolin-4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-5-yl,4-isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl,4-isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl,4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-5-yl,4-isothiazolin-5-yl, 2,3-dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl,2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl,2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-1-yl,3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl,3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-1-yl,4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl,4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl,2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl,3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3,4-dihydrooxazol-5-yl,3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl,2-, 3-, 4-, 5- or 6-di- or tetrahydropyridinyl, 3-di- ortetrahydropyridazinyl, 4-di- or tetrahydropyridazinyl, 2-di- ortetrahydropyrimidinyl, 4-di- or tetrahydropyrimidinyl, 5-di- ortetrahydropyrimidinyl, di- or tetrahydropyrazinyl, 1,3,5-di- ortetrahydrotriazin-2-yl, 1,2,4-di- or tetrahydrotriazin-3-yl,2,3,4,5-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl,3,4,5,6-tetrahydro[2H]azepin-2-, -3-, -4-, -5-, -6- or -7-yl,2,3,4,7-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl,2,3,6,7-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl,tetrahydrooxepinyl, such as 2,3,4,5-tetrahydro[1H]oxepin-2-, -3-, -4-,-5-, -6- or -7-yl, 2,3,4,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6-or -7-yl, 2,3,6,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6- or -7-yl,tetrahydro-1,3-diazepinyl, tetrahydro-1,4-diazepinyl,tetrahydro-1,3-oxazepinyl, tetrahydro-1,4-oxazepinyl,tetrahydro-1,3-dioxepinyl, tetrahydro-1,4-dioxepinyl,1,2,3,4,5,6-hexahydroazocine, 2,3,4,5,6,7-hexahydroazocine,1,2,3,4,5,8-hexahydroazocine, 1,2,3,4,7,8-hexahydroazocine,1,2,3,4,5,6-hexahydro-[1,5]diazocine,1,2,3,4,7,8-hexahydro-[1,5]diazocine and the like.

Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered maximally unsaturated(but not aromatic) heteromonocyclic ring are pyran-2-yl, pyran-3-yl,pyran-4-yl, thiopryran-2-yl, thiopryran-3-yl, thiopryran-4-yl,1-oxothiopryran-2-yl, 1-oxothiopryran-3-yl, 1-oxothiopryran-4-yl,1,1-dioxothiopryran-2-yl, 1,1-dioxothiopryran-3-yl,1,1-dioxothiopryran-4-yl, 2H-oxazin-2-yl, 2H-oxazin-3-yl,2H-oxazin-4-yl, 2H-oxazin-5-yl, 2H-oxazin-6-yl, 4H-oxazin-3-yl,4H-oxazin-4-yl, 4H-oxazin-5-yl, 4H-oxazin-6-yl, 6H-oxazin-3-yl,6H-oxazin-4-yl, 7H-oxazin-5-yl, 8H-oxazin-6-yl, 2H-1,3-oxazin-2-yl,2H-1,3-oxazin-4-yl, 2H-1,3-oxazin-5-yl, 2H-1,3-oxazin-6-yl,4H-1,3-oxazin-2-yl, 4H-1,3-oxazin-4-yl, 4H-1,3-oxazin-5-yl,4H-1,3-oxazin-6-yl, 6H-1,3-oxazin-2-yl, 6H-1,3-oxazin-4-yl,6H-1,3-oxazin-5-yl, 6H-1,3-oxazin-6-yl, 2H-1,4-oxazin-2-yl,2H-1,4-oxazin-3-yl, 2H-1,4-oxazin-5-yl, 2H-1,4-oxazin-6-yl,4H-1,4-oxazin-2-yl, 4H-1,4-oxazin-3-yl, 4H-1,4-oxazin-4-yl,4H-1,4-oxazin-5-yl, 4H-1,4-oxazin-6-yl, 6H-1,4-oxazin-2-yl,6H-1,4-oxazin-3-yl, 6H-1,4-oxazin-5-yl, 6H-1,4-oxazin-6-yl,1,4-dioxine-2-yl, 1,4-oxathiin-2-yl, 1H-azepine, 1H-[1,3]-diazepine,1H-[1,4]-diazepine, [1,3]diazocine, [1,5]diazocine, [1,5]diazocine andthe like.

Heteroaromatic monocyclic rings are in particular 5- or 6-membered.

Examples for 5- or 6-membered monocyclic heteroaromatic rings are2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl,1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl,4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl,1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl,1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl,1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl,1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl,2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl,1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl,1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl,1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl andthe like.

In the present invention, the “heterobicyclic rings” or “heterobicyclyl”contain two rings which have at least one ring atom in common. At leastone of the two rings contains a heteroatom or heteroatom group selectedfrom the group consisting of N, O, S, NO, SO and SO₂ as ring member. Theterm comprises condensed (fused) ring systems, in which the two ringshave two neighboring ring atoms in common, as well as spiro systems, inwhich the rings have only one ring atom in common, and bridged systemswith at least three ring atoms in common. In terms of the presentinvention, the heterobicyclic rings do not include throughout aromaticbicyclic ring systems; these are termed heteroaromatic bicyclic rings orbicycyclic het(ero)aryl or heterobiaryl. If in a condensed system onering is aromatic and the other is not and if the reaction in question isto take place on the aromatic moiety of the bicyclic system, these ringsare considered to belong to heteroaromatic rings (het(ero)aryl),although the system is not completely aromatic. The heterobicyclic ringsare preferably 7-, 8-, 9-, 10- or 11-membered. The heteroaromaticbicyclic rings are preferably 9-, 10- or 11-membered. Throughoutheteroaromatic heterobicyclic rings are 9- or 10-membered.

Examples for fused systems:

Examples for a 7-, 8-, 9-, 10- or 11-membered saturated heterobicyclicring containing 1, 2 or 3 (or 4) heteroatoms or heteroatom groupsselected from the group consisting of N, O, S, NO, SO and SO₂, as ringmembers are:

Examples for a 7-, 8-, 9-, 10- or 11-membered saturated heterobicyclicring containing 1, 2 or 3 (or 4) heteroatoms or heteroatom groupsselected from the group consisting of N, O, S, NO, SO and SO₂, as ringmembers are:

In the above examples, one ring is aromatic. If the reaction in questionis to take place on the aromatic moiety of the bicyclic system (or on afunctional group bound thereto), these rings are considered to belong toheteroaromatic rings (het(ero)aryl), although the system is notcompletely heteroaromatic.

Examples for a 7-, 8-, 9-, 10- or 11-membered maximally unsaturated (butnot throughout heteroaromatic) heterobicyclic ring containing 1, 2 or 3(or 4) heteroatoms or heteroatom groups selected from the groupconsisting of N, O, S, NO, SO and SO₂, as ring members are:

In the above examples, one ring is (hetero)aromatic. If the reaction inquestion is to take place on the (hetero)aromatic moiety of the bicyclicsystem (or on a functional group bound thereto), these rings areconsidered to belong to heteroaromatic rings (het(ero)aryl), althoughthe system is not completely heteroaromatic.

Examples for a 9- or 10-membered maximally unsaturated, throughoutheteroaromatic heterobicyclic ring containing 1, 2 or 3 (or 4)heteroatoms or heteroatom groups selected from the group consisting ofN, O, S, NO, SO and SO₂, as ring members are:

Examples for spiro-bound 7-, 8-, 9-, 10- or 11-membered heterobicyclicrings containing 1, 2 or 3 (or 4) heteroatoms or heteroatom groupsselected from the group consisting of N, O, S, NO, SO and SO₂, as ringmembers are

Examples for bridged 7-, 8-, 9-, 10- or 1-membered heterobicyclic ringscontaining 1, 2 or 3 (or 4) heteroatoms or heteroatom groups selectedfrom the group consisting of N, O, S, NO, SO and SO₂, as ring membersare

and the like.

In the above structures # denotes the attachment point to the remainderof the molecule. The attachment point is not restricted to the ring onwhich this is shown, but can be on either of the two rings, and may beon a carbon or on a nitrogen ring atom. If the rings carry one or moresubstituents, these may be bound to carbon and/or to nitrogen ringatoms.

Polycyclic heterocyclic rings (polyheterocyclyl) contain three or morerings, each of which having at least one ring atom in common with atleast one of the other rings of the polycyclic system. The rings can becondensed, spiro-bound or bridged; mixed systems (e.g. one ring isspiro-bound to a condensed system, or a bridged system is condensed withanother ring) are also possible. Throughout aromatic rings are notencompassed in the polycyclic heterocyclic ring (polyheterocyclyl);these are termed polycyclic heteroaromatic rings or heteropolyaryls.

If in a polycyclic system one ring is aromatic and (one of) the other(s)is/are not and if the reaction in question is to take place on thearomatic moiety of the polycyclic system (or on a functional group boundthereto), these rings are considered to belong to heteroaromatic rings(het(ero)aryl), although the system is not completely aromatic.

Aryloxy, heterocyclyloxy and heteroaryloxy (also expressed as O-aryl,O-heterocyclyl and O-heteroaryl) are aryl, heterocyclyl and heteroaryl,respectively, as defined above, bound via an oxygen atom to theremainder of the molecule. Examples are phenoxy or pyridyloxy.

If two radicals bound on the same nitrogen and, together with thisnitrogen atom, form a mono-, bi- or polycyclic heterocyclic ring (e.g.:in the Buchwald Hartwig reaction: R¹ and R³, together with the nitrogenatom they are bound to, may form a mono-, bi- or polycyclic heterocyclicring, or R⁴ and R⁵, together with the nitrogen atom they are bound to,may form a mono-, bi- or polycyclic heterocyclic ring; or in thecarboxamide or sulfonamide bond formation not requiring transition metalcatalysis R² and R³, together with the nitrogen atom they are bound to,may form a mono-, bi- or polycyclic heterocyclic ring; or in theprotection of primary or secondary amino groups R¹ and R², together withthe nitrogen atom they are bound to, may form a mono-, bi- or polycyclicheterocyclic ring) this ring, apart from the compulsory nitrogen atom,may contain 1, 2 or 3 or 4 further heteroatoms or heteroatom groupsselected from the group consisting of N, O, S, NO, SO or SO₂ as ringmembers. The ring may be saturated, partially unsaturated or maximallyunsaturated, including heteroaromatic. Monocyclic rings are inparticular 3- to 8-membered. Bicyclic rings are in particular 7- to20-membered, specifically 7- to 11-membered.

Examples of such monocyclic saturated heterocyclic rings areaziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrazolidin-1-yl,imidazolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl,isothiazolidin-2-yl, 1,2,4-oxadiazolidin-2-yl, 1,2,4-oxadiazolidin-4-yl,1,2,4-thiadiazolidin-2-yl, 1,2,4-thiadiazolidin-4-yl,1,2,4-triazolidin-1-yl, 1,2,4-triazolidin-4-yl,1,3,4-oxadiazolidin-3-yl, 1,3,4-thiadiazolidin-3-yl,1,3,4-triazolidin-1-yl, 1,3,4-triazolidin-3-yl, piperidin-1-yl,hexahydropyridazin-1-yl, hexahydropyrimidin-1-yl, 1 piperazin-1-yl, 11,3,5-hexahydrotriazin-1-yl, 1 1,2,4-hexahydrotriazin-1-yl,1,2,4-hexahydrotriazin-2-yl, 1,2,4-hexahydrotriazin-4-yl,morpholin-4-ylthiomorpholin-4-yl, 1-oxothiomorpholin-4-yl,1,1-dioxothiomorpholin-4-yl, azepan-1-yl, hexahydro-1,3-diazepin-1-yl,hexahydro-1,4-diazepin-1-yl, hexahydro-1,3-oxazepin-3-yl,hexahydro-1,4-oxazepin-4-yl, azocan-1-yl, [1,3]diazocan-1-yl,[1,4]diazocan-1-yl, [1,5]diazocan-1-yl, [1,5]oxazocan-1-yl and the like.

Examples of such monocyclic partially unsaturated heterocyclic ringsinclude: 2,3-dihydro-1H-pyrrol-1-yl, 2,5-dihydro-1H-pyrrol-1-yl,2,3-dihydro-1H-pyrazol-1-yl, 4,5-dihydro-1H-pyrazol-1-yl,2,3-dihydro-1H-imidazol-1-yl, 2,5-dihydro-1H-imidazol-1-yl,4,5-dihydro-1H-imidazol-1-yl, 2,3-dihydrooxazol-3-yl,2,3-dihydroisoxazol-2-yl, 2,5-dihydroisoxazol-2-yl,2,3-dihydrothiazol-3-yl, 2,3-dihydroisothiazol-2-yl,2,5-dihydroisothiazol-2-yl, 1,2-dihydropyridin-1-yl,1,4-dihydropyridin-1-yl, 1,2,3,4-tetrahydropyridin-1-yl,1,2,3,6-tetrahydropyridin-1-yl, 1,2,3,4-tetrahydropyridazin-1-yl,1,2,3,4-tetrahydropyridazin-2-yl, 1,2,3,6-tetrahydropyridazin-1-yl,1,2-dihydropyridazin-1-yl, 1,4-dihydropyridazin-1-yl,1,6-dihydropyridazin-1-yl, 1,2-dihydropyrimidin-1-yl,1,4-dihydropyrimidin-1-yl, 1,2,3,4-tetrahydropyrimidin-1-yl,1,2,3,4-tetrahydropyrimidin-3-yl, 1,2,5,6-tetrahydropyrimidin-1-yl,1,4,5,6-tetrahydropyrimidin-1-yl, 1,2-dihydropyrazin-1-yl,1,4-dihydropyrazin-1-yl, 1,2,3,4-tetrahydropyrazin-1-yl,1,2,3,6-tetrahydropyrazin-1-yl, 1,2-dihydro-1,3,5-triazin-1-yl,1,4-dihydro-1,3,5-triazin-1-yl, 1,2,3,4-tetrahydro-1,3,5-triazin-1-yl,1,2,3,4-tetrahydro-1,3,5-triazin-3-yl,2,3,4,5-tetrahydro-1H-azepin-1-yl, 2,3,4,7-tetrahydro-1H-azepin-1-yl,2,3,6,7-tetrahydro-1H-azepin-1-yl, 2,3-dihydro-1H-azepin-1-yl,2,5-dihydro-1H-azepin-1-yl, 4,5-dihydro-1H-azepin-1-yl,

Examples of such monocyclic maximally unsaturated heterocyclic,inclusive heteroaromatic, rings include 1-pyrrolyl, 1-pyrazolyl,1-imidazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-3-yl,1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1H-azepin-1-yl and the like.

Examples of such bicyclic heterocyclic rings are the above-depicted 7-,8-, 9-, 10- or 11-membered saturated, partially unsaturated or maximallyunsaturated fused, spiro-bound or bridged heterobicyclic rings whichcontain at least one secondary nitrogen atom (NH) as ring member and inwhich the attachment point to the remainder of the molecule (#) is onthis secondary nitrogen ring atom.

In the Baylis-Hillman reaction, R¹ and R² may form together with thecarbon atom they are bound to a carbocyclic or heterocyclic ring. Thisring may be saturated or partially unsaturated, monocyclic, bicyclic orpolycyclic. If this ring is heterocyclic, it contains 1, 2 or 3 or 4heteroatoms or heteroatom groups selected from the group consisting ofN, O, S, NO, SO or SO₂ as ring members.

For instance, R¹ and R² may form together —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—,—(CH₂)₆—, —CH═CH—, —CH═CH—CH₂—, —CH═CH—CH═CH—, —CH₂—CH═CH—CH₂—,—CH═CH—CH₂—CH═CH—, —CH₂—O—CH₂—CH₂—, —CH₂—N(R)—CH₂—CH₂—,—CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—N(R)—CH₂—CH₂—, and the like.

Sulfonates as leaving groups (as used, for example, in most of theabove-described transition-metal catalyzed C—C coupling reactions, likethe Suzuki, Sonogashira, Heck reactions etc.) are in general fluorinatedalkyl sulfonates, in particular fluorinated C₁-C₁₀-alkylsulfonates, moreparticularly perfluorinated C₁-C₁₀-alkylsulfonates, or aryl sulfonates,such as tosylate (p-toluene sulfonate). In particular they are triflate(trifluoromethane sulfonate), nonaflate (nonafluorobutyl sulfonate),heptadecafluorooctyl sulfonate or tosylate.

A metal equivalent M (as present for example in the boron compoundR¹—BF₃M) is a metal cation equivalent of formula (M^(n+))_(1/n), where Mis a metal, in particular an alkali metal, such as Li, Na or K, an earthalkaline metal, such as Mg or Ca, Al or a transition metal, such as Fe,Ni, Cu etc.

An acyl group in a group R—C(═O)—, where R is alkyl, alkenyl,alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, heterocyclyl, aryl or heteroaryl group, as definedabove, where this group may carry one or more substituents, as definedabove.

The invention will be further illustrated by the following, non-limitingexamples.

EXAMPLES Abbreviations

r.t. room temperature (20 to 25° C.)

TLC thin layer chromatography

LCMS liquid chromatography mass spectrometry

t-Bu, ^(t)Bu tert-butyl

O-t-Bu, O^(t)Bu tert-butanolate

KO-t-Bu, KO^(t)Bu potassium tert-butanolate

NaO-t-Bu, NaO^(t)Bu sodium tert-butanolate

OAc acetate

KOAc potassium acetate

EtOAc ethylacetate

OTf triflate

dtbpf 1,1′-bis(di-tert-butylphosphino)ferrocene

mida, MIDA N-methyliminodiacetic acid (see above)

Fmoc fluorenylmethoxycarbonyl

Val-OH L-valine

Fmoc-Val-OH N-(9-fluorenylmethoxycarbonyl)-L-valine

B₂pin₂ bis(pinacolato)diboron

In order to have reproducible conditions and exclude any (positive ornegative) influence from the water used (e.g. from traces of metal ormetal ions which may be present in common distilled water), Milli-Q®water was used. This Millipore Corporation trademark relates to‘ultrapure’ water of “Type 1”, as defined by various authorities (e.g.ISO 3696). The purification processes involve successive steps offiltration and deionization to achieve a purity expedientlycharacterised in terms of resistivity (typically 18 MΩ·cm at 25° C.). Inthe present case it was obtained with an EMD Millipore Milli-Q™Advantage A10 water purification system from EMD Millipore Z00Q0V0US.This water is termed in the following “Millipore water”. But thereactions of the present invention can of course also be carried outwith “normal” distilled water as used in any laboratory or industry oralso just with tap water.

Preliminary Remarks

The viscosities of the cellulose derivatives given in the below examplesare the values given by the respective suppliers of a 2% by weightsolution at 20° C. They coincide well with the values obtained with themethods described above (for 1-70 mPa·s: Malvern Instruments Viscosizer200 and an uncoated glass capillary; 25° C.; for >70-4000 mPa·s:falling-sphere viscosimeter; 25° C.; for >4000 mPa·s: single-cylindertype spindle viscosimeter; 20° C.Following cellulosic products were used:

Viscosity given by Determined supplier viscosity Commercial [mPa · s[mPa · s Product product name Supplier or cps] or cps] HPMC Mantrocel E52910 Parmentier 4-6 3.9 HPMC Hydroxypropyl Sigma- 40-60 methyl celluloseAldrich 40-60 HPMC Hydroxypropyl Alfa Aesar 40-60 42.8 methyl cellulose40-60 HPMC Hydroxypropyl Sigma-  80-120 77.3 methyl cellulose Aldrich80-120 HPMC Hydroxypropyl Sigma- 2600-5600 methyl cellulose Aldrich2600-5600 HPMC Methocel E4M Colorcon 3000-5600 Premium EP GmbH HPMCMantrocel K4M Parmentier 4100  3263 GmbH MC Methyl cellulose Sigma-  25M6385 Aldrich MC Methyl cellulose Sigma-  15 M7140 Aldrich MC Methylcellulose ABCR 1600  AB211131 HEC Hydroxyethylcellulose Sigma-  80-125Aldrich HEC Hydroxyethylcellulose Sigma- 145 Aldrich HPCHydroxypropylcellulose ABCR 3-5 AB137066 HPC HydroxypropylcelluloseSigma-  75-150* 191884 Aldrich HECE Polyquatemium 10 Sigma- 400 AldrichMH Tylose MH300 Sigma- 150-450 Aldrich *determined at 25° C.; 5% in H₂OHPMC hydroxypropylmethylcellulose MC methylcellulose HEChydroxyethylcellulose HPC hydroxypropylcellulose HECE Polyquaternium-10;hydroxyethylcellulose ethoxylate (quaternized hydroxyethyl cellulose)Tylose MH300 methyl-2-hydroxyethylcellulose

I. General Procedure for the Preparation of the Aqueous OligosaccharideSolutions (Per 100 ml)

66 ml of Millipore water was heated to 70° C. under stirring in areaction flask. The appropriate amount of an oligosaccharide was added.Subsequently 34 ml of Millipore water was added and the reaction mixturewas allowed to cool to room temperature under stirring. The solution waspurged with Argon for 30 minutes.

A. Procedure for the Preparation of 2% HPMC (40-60 cps=mPa·s) in Water(Per 100 ml):

66 ml of Millipore water was heated to 70° C. under stirring in areaction flask. 2 g of HPMC (40-60 cps) were added. The reaction mixtureformed a cloudy solution. Subsequently 34 ml of Millipore water wasadded and the reaction mixture was allowed to cool to room temperatureunder stirring to form a clear solution. The solution was purged withArgon for 30 minutes.

B. Procedure for the Preparation of 5% HPMC (40-60 cps) in Water (Per100 ml):

66 ml of Millipore water was heated to 70° C. under stirring in areaction flask. 5 g of HPMC (40-60 cps) were added. The reaction mixtureformed a cloudy solution. Subsequently 34 ml of Millipore water wasadded and the reaction mixture was allowed to cool to room temperatureunder stirring to form a clear solution. The solution was purged withArgon for 30 minutes.

C. Procedure for the Preparation of 3% HPMC (40-60 cps) in Water (Per100 ml):

66 ml of Millipore water was heated to 70° C. under stirring in areaction flask. 3 g of HPMC (40-60 cps) were added. The reaction mixtureformed a cloudy solution. Subsequently 34 ml of Millipore water wasadded and the reaction mixture was allowed to cool to room temperatureunder stirring to form a clear solution. The solution was purged withArgon for 30 minutes.

D. Procedure for the Preparation of 1% HPMC (40-60 cps) in Water (Per100 ml):

66 ml of Millipore water was heated to 70° C. under stirring in areaction flask. 1 g of HPMC (40-60 cps) were added. The reaction mixtureformed a cloudy solution. Subsequently 34 ml of Millipore water wasadded and the reaction mixture was allowed to cool to room temperatureunder stirring to form a clear solution. The solution was purged withArgon for 30 minutes.

E. Procedure for the Preparation of 0.5% HPMC (40-60 cps) in Water (Per100 ml):

66 ml of Millipore water was heated to 70° C. under stirring in areaction flask. 500 mg of HPMC (40-60 cps) were added. The reactionmixture formed a cloudy solution. Subsequently 34 ml of Millipore waterwas added and the reaction mixture was allowed to cool to roomtemperature under stirring to form a clear solution. The solution waspurged with Argon for 30 minutes.

Other oligosaccharides were prepared analogously.

II. Preparation Examples

¹H-NMR: The signals are characterized by chemical shift (ppm) vs.tetramethylsilane, by their multiplicity and by their integral (relativenumber of hydrogen atoms given). The following abbreviations are used tocharacterize the multiplicity of the signals: m=multiplett, q=quartett,t=triplett, d=doublet, s=singlett, dd=doublet of doublets, dt=doublet oftripletts, dq=doublet of quartetts, ddd=doublet of doublets of doublets,td=triplett of doublets, tdd=triplett of doublets of doublets;tt=triplett of tripletts, br or=broad (e.g. s_(br) or bs=broadsinglett).

1. Buchwald-Hartwig Reactions General Procedure for Buchwald-HartwigAminations I

[(π-allyl)PdCl]₂ catalyst (0.005 eq), a phosphine ligand (0.020 eq) anda base (1.50 eq) were added under an Argon atmosphere into a 5.0 mLmicrowave vial containing a magnetic stir bar and Teflon-lined septum.HPMC in water solution (40-60 cps, 3 ml of 2 wt % in degassed Milliporewater) was added under a positive flow of argon, followed by theaddition of the amine (1.20 eq) and subsequently of the aryl bromide(1.0 eq) (however, any liquid components were always added after thesolvent). The reaction mixture was stirred at 1200 rpm for the indicatedtime at the indicated temperature. To the reaction mixture were addedethyl acetate and saturated aqueous sodium sulfate solution. The organicphase was separated from the solid. The solid was washed three timeswith ethyl acetate. The combined ethyl acetate phases were dried invacuo and the residue was further purified by flash chromatography onsilica gel.

General Procedure for Buchwald-Hartwig Aminations II

An amine (1.2 eq), an aryl bromide (1.0 eq), [(π-allyl)PdCl]₂ catalyst(0.005 eq), a phosphine ligand (0.020 eq) and a base (1.50 eq) wereadded under an Argon atmosphere into a 5.0 mL microwave vial containinga magnetic stir bar and Teflon-lined septum. HPMC in water solution(40-60 cps, 3 ml of 2 wt % in degassed Millipore water) was added undera positive flow of argon (however, any liquid components were alwaysadded after the solvent). The reaction mixture was stirred at 1200 rpmfor the indicated time at the indicated temperature. To the reactionmixture were added ethyl acetate and saturated aqueous sodium sulfatesolution. The organic phase was separated from the solid. The solid waswashed three times with ethyl acetate. The combined ethyl acetate phaseswere dried in vacuo and the residue was further purified by flashchromatography on silica gel (0-30% ethyl acetate/heptane).

1.1 Preparation of N-(p-tolyl)naphthalen-2-amine According to theGeneral Procedure I

Following the general procedure I using [(π-allyl)PdCl]₂ catalyst (1.8mg, 0.005 mmol),di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP) ligand(7.0 mg, 0.020 mmol), KO-t-Bu (168 mg, 1.50 mmol), a HPMC-solution(40-60 cps, 3 ml of 2 wt % in degassed Millipore water), p-toluidine(129 mg, 1.20 mmol) and naphthyl bromide (211 mg, 1.0 mmol). Thereaction mixture was stirred at 1200 rpm for 4 h at room temperatureLC-MS indicated however that the reaction was already completed after 2h. To the reaction mixture were added 20 ml of ethyl acetate and 3 ml ofsaturated aqueous sodium sulfate solution. The organic phase wasseparated from the solid. The solid was washed three times with ethylacetate. The combined ethyl acetate phases were dried in vacuo and theresidue was further purified by flash chromatography on silica gel(0-30% ethyl acetate/heptane). The desired product was obtained as anoff-white solid (211 mg, 88% yield).

ESI-MS: m/z (%): 234.20 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.70 (m, 2H), 7.60 (m, 1H), 7.40 (m,2H), 7.30 (m, 1H), 7.20 (m, 1H), 7.15 (m, 2H), 7.10 (m, 2H), 5.80(s_(br), 1H), 2.30 (s, 3H).

1.2 Preparation of N-(p-tolyl)naphthalen-2-amine According to theGeneral Procedure II

Following the general procedure II using p-toluidine (129 mg, 1.20mmol), naphthyl bromide (211 mg, 1.0 mmol), [(π-allyl)PdCl]₂ catalyst(1.8 mg, 0.005 mmol),di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP) ligand(7.0 mg, 0.020 mmol), KO-t-Bu (168 mg, 1.50 mmol) and a HPMC-solution(40-60 cps, 3 ml of 2 wt % in degassed Millipore water) were stirred at1200 rpm for 15 min. at 50° C. To the reaction mixture were added 20 mlof ethyl acetate and 3 ml of saturated aqueous sodium sulfate solution.The organic phase was separated from the solid. The solid was washedthree times with ethyl acetate. The combined ethyl acetate phases weredried in vacuo and the residue was further purified by flashchromatography on silica gel (0-30% ethyl acetate/heptane). The desiredproduct was obtained as an off-white solid (224 mg, 90% yield, 94%purity).

ESI-MS: m/z (%): 234.20 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.70 (m, 2H), 7.60 (m, 1H), 7.35 (m,2H), 7.25 (m, 1H), 7.20 (m, 1H), 7.15 (m, 2H), 7.10 (m, 2H), 5.85(s_(br), 1H), 2.35 (s, 3H).

1.3 Preparation of 4-methoxy-N-(p-tolyl)aniline According to GeneralProcedure II

1.3.1) According to the general procedure II, p-toluidine (129 mg, 1.20mmol), 1-bromo-4-methoxybenzene (189 mg, 1.0 mmol), [(π-allyl)PdCl]₂catalyst (1.8 mg, 0.005 mmol),di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP) ligand(7.0 mg, 0.020 mmol), KO-t-Bu (168 mg, 1.50 mmol) and a HPMC-solution(40-60 cps, 3 ml of 2 wt % in degassed Millipore water) were stirred at1200 rpm overnight at room temperature. To the reaction mixture wereadded 20 ml of ethyl acetate and 3 ml of saturated aqueous sodiumsulfate solution. The organic phase was separated from the solid. Thesolid was washed three times with ethyl acetate. The combined ethylacetate phases were dried in vacuo and the residue was further purifiedby flash chromatography on silica gel (0-100% ethylacetate/cyclohexane). The desired product was obtained as an off-whitesolid (213 mg, 100% yield).

1.3.2) According to the general procedure II, p-toluidine (129 mg, 1.20mmol), 1-bromo-4-methoxybenzene (189 mg, 1.0 mmol), [(π-allyl)PdCl]₂catalyst (1.8 mg, 0.005 mmol),di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP) ligand(7.0 mg, 0.020 mmol, KO-t-Bu (168 mg, 1.50 mmol) and HPMC-solution(40-60 cps, 3 ml of 2 wt % in degassed Millipore water) were stirred at1200 rpm for 1 h at 50° C. To the reaction mixture were added 20 ml ofethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. Theorganic phase was separated from the solid. The solid was washed threetimes with ethyl acetate. The combined ethyl acetate phases were driedin vacuo and the residue was further purified by flash chromatography onsilica gel (0-100% ethyl acetate/cyclohexane). The desired product wasobtained as an off-white solid (209 mg, 98% yield).

1.3.3) According to the general procedure II, p-toluidine (129 mg, 1.20mmol), 1-bromo-4-methoxybenzene (189 mg, 1.0 mmol), [(π-allyl)PdCl]₂catalyst (1.8 mg, 0.005 mmol),di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP) ligand(7.0 mg, 0.020 mmol), KO-t-Bu (168 mg, 1.50 mmol) and a HPMC-solution(4-6 cps, 3 ml of 2 wt % in degassed Millipore water) were stirred at1200 rpm for 40 min at 50° C. To the reaction mixture were added 20 mlof ethyl acetate and 3 ml of saturated aqueous sodium sulfate solution.The organic phase was separated from the solid. The solid was washedthree times with ethyl acetate. The combined ethyl acetate phases weredried in vacuo and the residue was further purified by flashchromatography on silica gel (0-100% ethyl acetate/cyclohexane). Thedesired product was obtained as an off-white solid (204 mg, 96% yield).

1.3.4) According to the general procedure II, p-toluidine (129 mg, 1.20mmol), 1-bromo-4-methoxybenzene (189 mg, 1.0 mmol), [(π-allyl)PdCl]₂catalyst (1.8 mg, 0.005 mmol),di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP) ligand(7.0 mg, 0.020 mmol), KO-t-Bu (168 mg, 1.50 mmol) and a HPMC-solution(4-6 cps, 0.35 ml of 2 wt % in degassed Millipore water) were stirred at1200 rpm for 9 min at 50° C. To the reaction mixture were added 20 ml ofethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. Theorganic phase was separated from the solid. The solid was washed threetimes with ethyl acetate. The combined ethyl acetate phases were driedin vacuo and the residue was further purified by flash chromatography onsilica gel (0-100% ethyl acetate/cyclohexane). The desired product wasobtained as an off-white solid (183 mg, 86% yield).

ESI-MS: m/z (%): 214.20 (100, [M+H]⁺).

¹H NMR (600 MHz, d⁶-DMSO): δ [ppm]: 7.68 (s, 1H), 7.01-6.95 (m, 4H),6.87-6.80 (m, 4H), 3.70 (s, 3H), 2.19 (s, 3H).

1.4 Preparation of 4-methoxy-N-(m-tolyl)benzamide

1.4.1) According to the general procedure II, 4-methoxybenzamide (181mg, 1.20 mmol), 3-bromo-toluene (171 mg, 0.98 mmol), [(π-allyl)PdCl]₂catalyst (5.6 mg, 0.011 mmol),di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine(tBuXPhos) ligand (18.3 mg, 0.043 mmol), NaO-t-Bu (141 mg, 1.50 mmol)and a HPMC-solution (40-60 cps, 3 ml of 2 wt % in degassed Milliporewater) were stirred at 1200 rpm for 5 h at room temperature. To thereaction mixture were added 20 ml of ethyl acetate and 3 ml of saturatedaqueous sodium sulfate solution. The organic phase was separated fromthe solid. The solid was washed three times with ethyl acetate. Thecombined ethyl acetate phases were dried in vacuo and the residue wasfurther purified by flash chromatography on silica gel (0-100% ethylacetate/cyclohexane). The desired product was obtained as an off-whitesolid (209 mg, 89% yield).

1.4.2) According to the general procedure II, 4-methoxybenzamide (181mg, 1.20 mmol), 3-bromo-toluene (171 mg, 0.98 mmol), [(π-allyl)PdCl]₂catalyst (5.6 mg, 0.011 mmol),di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine(tBuXPhos) ligand (18.3 mg, 0.043 mmol), NaO-t-Bu (141 mg, 1.50 mmol)and a HPMC-solution (40-60 cps, 3 ml of 2 wt % in degassed Milliporewater) were stirred at 1200 rpm for 30 min at 50° C. To the reactionmixture were added 20 ml of ethyl acetate and 3 ml of saturated aqueoussodium sulfate solution. The organic phase was separated from the solid.The solid was washed three times with ethyl acetate. The combined ethylacetate phases were dried in vacuo and the residue was further purifiedby flash chromatography on silica gel (0-100% ethylacetate/cyclohexane). The desired product was obtained as an off-whitesolid (230 mg, 97% yield).

1.4.3) According to the general procedure II, 4-methoxybenzamide (181mg, 1.20 mmol), 3-bromo-toluene (171 mg, 0.98 mmol), [(π-allyl)PdCl]₂catalyst (5.6 mg, 0.011 mmol),di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine(tBuXPhos) ligand (18.3 mg, 0.043 mmol), NaO-t-Bu (141 mg, 1.50 mmol)and a HPMC-solution (4-6 cps, 2 wt % in 0.35 ml degassed Milliporewater) were stirred at 1200 rpm for 30 min at 50° C. To the reactionmixture were added 20 ml of ethyl acetate and 3 ml of saturated aqueoussodium sulfate solution. The organic phase was separated from the solid.The solid was washed three times with ethyl acetate. The combined ethylacetate phases were dried in vacuo and the residue was further purifiedby flash chromatography on silica gel (0-100% ethylacetate/cyclohexane). The desired product was obtained as an off-whitesolid (221 mg, 89% yield, 95% purity).

ESI-MS: m/z (%): 242.20 (100, [M+H]⁺).

¹H NMR (600 MHz, d₆-DMSO): δ [ppm]: 10.01 (s, 1H), 7.99-7.92 (m, 2H),7.61 (d, J=1.8 Hz, 1H), 7.59-7.53 (m, 1H), 7.22 (t, J=7.8 Hz, 1H),7.09-7.03 (m, 2H), 6.90 (d, J=7.5 Hz, 1H), 3.84 (s, 3H), 2.30 (s, 3H).

1.5 Preparation of ethyl-4-((tert-butoxycarbonyl)amino)benzoate

1.5.1) According to the general procedure I, tert-butyl carbamate (176mg, 1.50 mmol), ethyl 4-bromobenzoate (229 mg, 1.00 mmol),[(π-allyl)PdCl]₂ catalyst (1.8 mg, 0.005 mmol),di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP) ligand(7.1 mg, 0.020 mmol), NaO-t-Bu (144 mg, 1.50 mmol) and a HPMC-solution(40-60 cps, 3 ml of 2 wt % in degassed Millipore water) were stirred at1200 rpm for 1 h at room temperature. To the reaction mixture were added20 ml of ethyl acetate and 3 ml of saturated aqueous sodium sulfatesolution. The organic phase was separated from the solid. The solid waswashed three times with ethyl acetate. The combined ethyl acetate phaseswere dried in vacuo and the residue was further purified by flashchromatography on silica gel (0-100% ethyl acetate/cyclohexane). Thedesired product was obtained as an off-white solid (220 mg, 79% yield).

1.5.2) According to the general procedure I, tert-butyl carbamate (176mg, 1.50 mmol), ethyl 4-bromobenzoate (229 mg, 1.00 mmol),[(π-allyl)PdCl]₂ catalyst (1.8 mg, 0.005 mmol),di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP) ligand(7.1 mg, 0.020 mmol), NaO-t-Bu (144 mg, 1.50 mmol) and a HPMC-solution(40-60 cps, 3 ml of 2 wt % in degassed Millipore water) were stirred at1200 rpm for 15 min at 50° C. To the reaction mixture were added 20 mlof ethyl acetate and 3 ml of saturated aqueous sodium sulfate solution.The organic phase was separated from the solid. The solid was washedthree times with ethyl acetate. The combined ethyl acetate phases weredried in vacuo and the residue was further purified by flashchromatography on silica gel (0-100% ethyl acetate/cyclohexane). Thedesired product was obtained as an off-white solid (225 mg, 85% yield).

1.5.3) According to the general procedure I, tert-butyl carbamate (176mg, 1.50 mmol), ethyl 4-bromobenzoate (229 mg, 1.00 mmol),[(π-allyl)PdCl]₂ catalyst (1.8 mg, 0.005 mmol),di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP) ligand(7.1 mg, 0.020 mmol), NaO-t-Bu (144 mg, 1.50 mmol) and a HPMC-solution(4-6 cps, 0.35 ml of 2 wt % in degassed Millipore water) were stirred at1200 rpm for 4 min at 50° C. To the reaction mixture were added 20 ml ofethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. Theorganic phase was separated from the solid. The solid was washed threetimes with ethyl acetate. The combined ethyl acetate phases were driedin vacuo and the residue was further purified by flash chromatography onsilica gel (0-100% ethyl acetate/cyclohexane). The desired product wasobtained as an off-white solid (275 mg, 98% yield).

ESI-MS: m/z (%): 210.20 (100, [M+H-t-Bu]⁺), 266.25 (75, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 8.00 (m, 2H), 7.45 (m, 2H), 6.65(s_(br), 1H), 4.35 (m, 2H), 1.50 (s, 9H), 1.40 (m, 3H).

1.6 Preparation of tert-butyl pyrimidin-5-ylcarbamate

According to the general procedure I, tert-butyl carbamate (176 mg, 1.50mmol), 5-bromopyrimidine (164 mg, 1.00 mmol), [Pd(1-phenylallyl)Cl]₂catalyst (10.4 mg, 0.02 mmol),di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine(tBuXPhos) ligand (17.0 mg, 0.04 mmol), potassium hydroxide (84 mg, 1.50mmol), triisopropylsilanol (267 mg, 1.50 mmol) and a HPMC-solution (4-6cps, 0.333 ml of 2 wt % in degassed Millipore water) were stirred at1200 rpm for 45 min at 50° C. To the reaction mixture was added bulksorbents (diatomaceous earth; mean particle size: 150-850 μm; poresize/porosity; 60 A; Telos® NM from Kinesis Bulk Media). The solid wasthen added on top of a silica gel chromatography cartridge and wasfurther purified by flash chromatography on silica gel (0-40% ethyldichloromethane/methanol). The desired product was obtained as anoff-white solid (191 mg, 83% yield, 85% purity).

APCI-MS: m/z (%): 196.20 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 8.95 (s, 1H), 8.85 (s, 2H), 6.50(s_(br), 1H), 1.55 (s, 9H).

1.7 Preparation of 6-methyl-N-(3-phenylpropyl)pyridine-2-amine

1.7.1) According to the general procedure II, 3-phenylpropylamine (162mg, 1.20 mmol), 2-chloro-6-methylpyridine (128 mg, 1.00 mmol),[(π-allyl)PdCl]₂ catalyst (5.7 mg, 0.011 mmol),di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine(t-BuXPhos) ligand (18.8 mg, 0.044 mmol) NaO-t-Bu (145 mg, 1.50 mmol)and a HPMC-solution (40-60 cps, 1 ml of 2 wt % in degassed Milliporewater) were stirred at 1200 rpm for 5 h at room temperature. To thereaction mixture were added 20 ml of ethyl acetate and 3 ml of saturatedaqueous sodium sulfate solution. The organic phase was separated fromthe solid. The solid was washed three times with ethyl acetate. Thecombined ethyl acetate phases were dried in vacuo and the residue wasfurther purified by flash chromatography on silica gel (0-100% ethylacetate/cyclohexane). The desired product was obtained as an off-whitesolid (150 mg, 66% yield).

1.7.2) According to the general procedure II, 3-phenylpropylamine (162mg, 1.20 mmol), 2-chloro-6-methylpyridine (128 mg, 1.00 mmol),[(π-allyl)PdCl]₂ catalyst (5.7 mg, 0.011 mmol),di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine(t-BuXPhos) ligand (18.8 mg, 0.044 mmol), NaO-t-Bu (145 mg, 1.50 mmol)and a HPMC-solution (40-60 cps, 1 ml of 2 wt % in degassed Milliporewater) were stirred at 1200 rpm for 3 h at 50° C. To the reactionmixture were added 20 ml of ethyl acetate and 3 ml of saturated aqueoussodium sulfate solution. The organic phase was separated from the solid.The solid was washed three times with ethyl acetate. The combined ethylacetate phases were dried in vacuo and the residue was further purifiedby flash chromatography on silica gel (0-100% ethylacetate/cyclohexane). The desired product was obtained as an off-whitesolid (183 mg, 81% yield).

ESI-MS: m/z (%): 227.20 (100, [M+H]⁺).

¹H NMR (600 MHz, d₆-DMSO): δ [ppm]: 7.31-7.24 (m, 2H), 7.27-7.19 (m,3H), 7.21-7.14 (m, 1H), 6.38 (t, J=5.5 Hz, 1H), 6.30 (d, J=7.1 Hz, 1H),6.22 (d, J=8.3 Hz, 1H), 3.23-3.16 (m, 2H), 2.68-2.61 (m, 2H), 2.23 (s,3H), 1.81 (tt, J=7.5, 6.4 Hz, 2H).

General Procedure for Buchwald-Hartwig Reactions Using Sulfonamides

To allylpalladium chloride dimer (0.02 equiv.),di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (0.04 equiv.),NaO^(t)Bu (1.5 equiv.) and the sulfonamide (1.2 equiv.) under an argonatmosphere was added 2 wt % solution of HPMC (40-60 cps) in Milliporewater and the arylbromide (1.0 equiv.). The reaction was stirred underan argon atmosphere for the indicated time at the indicated temperature.The mixture was diluted with EtOAc (3 mL) and then with a sat. solutionof Na₂SO₄ (3 mL). After Extraction with EtOAc (1×15 mL), the mixture wasbrought to pH 3 by using a 5% solution of citric acid in water (3 mL)and extracted again using EtOAc (2×15 mL). The clean product wasobtained after flash chromatography on silica gel.

1.8 Preparation of ethyl 4-(methylsulfonamido)benzoate

1.8.1) Following the general procedure using ethyl 4-bromobenzoate (229mg, 1.00 mmol, 1.0 equiv.), methanesulfonamide (114 mg, 1.20 mmol, 1.2equiv.), allylpalladium chloride dimer (7.3 mg, 0.02 mmol, 0.02 equiv.),di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (14 mg, 0.04mmol, 0.04 equiv.), NaO^(t)Bu (144 mg, 1.50 mmol, 1.5 equiv.) and a HPMCsolution (40-60 cps, 1 ml of 2 wt % in degassed Millipore water) thereaction was allowed to stir vigorously under an argon atmosphere for 6h at 50° C., 20 h at room temperature, 6 h at 50° C. and again for 20 hat room temperature. After column chromatography (0-50% EtOAc/heptane),the product was obtained (158 mg, 0.65 mmol, 65%).

1.8.2) Following the general procedure using ethyl 4-bromobenzoate (229mg, 1.00 mmol, 1.0 equiv.), methanesulfonamide (114 mg, 1.20 mmol, 1.2equiv.), allylpalladium chloride dimer (7.3 mg, 0.02 mmol, 0.02 equiv.),di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (14 mg, 0.04mmol, 0.04 equiv.), NaO^(t)Bu (144 mg, 1.50 mmol, 1.5 equiv.) and aHPMC-solution (40-60 cps, 0.333 ml of 2 wt % in degassed Milliporewater) the reaction was allowed to stir vigorously under an argonatmosphere for 6 h at 50° C., 20 h at room temperature, 6 h at 50° C.and again for 20 h at room temperature. After column chromatography(0-50% EtOAc/heptane), the product was obtained (158 mg, 0.65 mmol,65%).

ESI-MS: m/z (%): 244.0 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 8.10-7.97 (m, 2H), 7.25-7.21 (m, 2H),6.61 (s_(br), 1H), 4.37 (q, J=7.1 Hz, 2H), 3.09 (s, 3H), 1.39 (t, J=7.1Hz, 3H).

General Procedure for Buchwald-Hartwig Reactions Using Urea Derivatives

To allylpalladium chloride dimer (0.02 equiv.),di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (0.04 equiv.),KOH (1.5 equiv.) and the urea derivative (1.2 equiv.) under an argonatmosphere was added a 2 wt % solution of HPMC in Millipore water, thearylbromide (1.0 equiv.) and finally TIPS-OH (1.2 equiv.). The reactionwas stirred under an argon atmosphere for the indicated time at theindicated temperature. The mixture was diluted with EtOAc (3 mL) andthen with a sat. solution of Na₂SO₄ (3 mL). After Extraction with EtOAc(up to 9×5 mL), the crude product was purified by flash chromatographyon silica gel.

1.9 Preparation of ethyl 4-(piperidine-1-carboxamido)benzoate

1.9.1) Following the general procedure using ethyl 4-bromobenzoate (229mg, 1.00 mmol, 1.0 equiv.), piperidine-1-carboxamide (159 mg, 1.20 mmol,1.2 equiv.), allylpalladium chloride dimer (7.2 mg, 0.02 mmol, 0.02equiv.), di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (14mg, 0.04 mmol, 0.04 equiv.), KOH (82 mg, 1.50 mmol, 1.5 equiv.),triisopropylsilanol (261 mg, 1.50 mmol, 1.5 equiv.) and a 2 wt %solution of HPMC (40-60 cps) in Millipore water (2.0 mL) the reactionwas allowed to stir vigorously under an argon atmosphere for 2.5 h at50° C. After column chromatography (0-50% EtOAc/heptane), the productwas obtained (249 mg, 0.88 mmol, 89%).

1.9.2) Following the general procedure using ethyl 4-bromobenzoate (229mg, 1.00 mmol, 1.0 equiv.), piperidine-1-carboxamide (159 mg, 1.20 mmol,1.2 equiv.), allylpalladium chloride dimer (7.2 mg, 0.02 mmol, 0.02equiv.), di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (14mg, 0.04 mmol, 0.04 equiv.), KOH (82 mg, 1.50 mmol, 1.5 equiv.),triisopropylsilanol (261 mg, 1.50 mmol, 1.5 equiv.) and a 2 wt %solution of HPMC (4-6 cps) in Millipore water (0.33 mL) the reaction wasallowed to stir vigorously under an argon atmosphere for 40 min at 50°C. After column chromatography (0-50% EtOAc/heptane), the product wasobtained (276 mg, 0.95 mmol, 97%).

ESI-MS: m/z (%): 277.1 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 8.00-7.94 (m, 2H), 7.47-7.42 (m, 2H),6.53 (s_(br), 1H), 4.35 (q, J=7.1 Hz, 2H), 3.50-3.44 (m, 4H), 1.70-1.60(m, 6H), 1.38 (t, J=7.1 Hz, 3H).

1.10 Preparation of N-(p-tolyl)naphthalen-2-amine Using HPMC in VariousConcentrations

[(π-allyl)PdCl]₂ catalyst (1.8 mg, 0.005 mmol),di-tert-butyl(1-methyl-2,2-diphenyl-cyclopropyl)phosphine (cBRIDP)ligand (7.0 mg, 0.020 mmol) and KO-t-Bu as base (168 mg, 1.50 mmol) wereadded under an Argon atmosphere into a 5.0 mL microwave vial containinga magnetic stir bar and Teflon-lined septum. As solvent an HPMC (40-60cps)-water solution (specifications & volume see table below) was addedunder a positive flow of Argon, followed by the addition of p-toluidine(129 mg, 1.20 mmol) and subsequently naphthyl bromide (211 mg, 1.0mmol). The reaction mixture was stirred at 1200 rpm for the indicatedtime (see table below) at 50° C. To the reaction mixture were addedethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. Theorganic phase was separated from the solid. The solid was extractedthree times with ethyl acetate. The combined ethyl acetate phases weredried in vacuo and the residue was further purified by flashchromatography on silica gel (0-30% ethyl acetate/heptane). The desiredproduct was obtained as an off-white solid.

Amount Viscosity Volume Molarity Reaction Ex. No. HPMC solvent solventreaction¹ time Yield² 1.10.1 0.2 wt % 1.02 cps 3.00 mL 0.33M 30 min 87%1.10.2 0.2 wt % 1.02 cps 0.35 mL 2.86M 90 sec  92% 1.10.3 2.0 wt % 42.88cps 3.00 mL 0.33M 15 min 90% 1.10.4 2.0 wt % 42.88 cps 0.35 mL 2.86M 90sec  98% ¹mol naphthyl bromide per 11 of solvent ²realtive to naphthylbromide

The same reaction as in 1.10.3 and 1.10.4 was carried out at roomtemperature. The results are compiled in the following table:

Amount Viscosity Volume Molarity Reaction Ex. No. HPMC solvent solventreaction¹ time Yield² 1.10.5 2.0 wt % 42.88 cps 3.00 mL 0.33M 3 h 91%1.10.6 2.0 wt % 42.88 cps 0.35 mL 2.86M 5 min 97% ¹mol naphthyl bromideper 11 of solvent ²realtive to naphthyl bromide

1.11 Preparation of N-(p-tolyl)naphthalen-2-amine Using HPMCs of VariousViscosities and Other Cellulose Derivatives

[(π-allyl)PdCl]₂ catalyst (1.8 mg, 0.005 mmol),di-tert-butyl(I-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP) ligand(7.0 mg, 0.020 mmol) and KO-t-Bu as base (168 mg, 1.50 mmol) were addedunder an argon atmosphere into a 5.0 mL microwave vial containing amagnetic stir bar and Teflon-lined septum. A 2 wt % solution ofcellulose derivative in Millipore water (molarity of the reaction: 0.3M, specifications of the cellulose derivative: see table below) wasadded under a positive flow of Argon, followed by the addition ofp-toluidine (129 mg, 1.20 mmol) and subsequently naphthyl bromide (211mg, 1.0 mmol). The reaction mixture was stirred at 1200 rpm until fullconversion (followed by LCMS, see table below) at 50° C. To the reactionmixture were added ethyl acetate and 3 ml of saturated aqueous sodiumsulfate solution. The organic phase was separated from the solid. Thesolid was washed three times with ethyl acetate. The combined ethylacetate phases were dried in vacuo and the residue was further purifiedby flash chromatography on silica gel (0-30% ethyl acetate/heptane). Thedesired product was obtained as an off-white solid.

Reaction Ex. No. Cellulose derivative Temperature time Yield 1.11.1 HPMC(4.8-7.2 cps) RT 3 h 90% 1.11.2 HPMC (80-120 cps) RT 72 h 89% 1.11.3HPMC (2600-5600 cps) RT 6.5 h 92% 1.11.4 HPMC (3000-5600 cps) RT 3 h 93%1.11.5 HPMC (4100 cps) RT 1 h 89% 1.11.6 MC (25 cps) RT 4 h 94% 1.11.7HPMC (4-6 cps) 50° C. 15 min 89% 1.11.8 HPMC (40-60 cps) 50° C. 15 min90% 1.11.9 MC (15 cps) 50° C. 15 min 92% 1.11.10 MC (1600 cps) 50° C. 5min 88% 1.11.11 HEC (80-125 cps) 50° C. 20 min 89% 1.11.12 HEC (145 cps)50° C. 6 min 95% 1.11.13 HECE (Polyquat. 10) 50° C. 12 min 94% 1.11.14HPC (3-5 cps) 50° C. 15 min 92% 1.11.15 HPC (75-150 cps) 50° C. 20 min84% 1.11.16 Tylose MH300 50° C. 25 min 94% HPMChydroxypropylmethylcellulose MC methylcellulose HEChydroxyethylcellulose HPC hydroxypropylcellulose HECE Polyquaternium-10;hydroxyethylcellulose ethoxylate (quaternized hydroxyethyl cellulose)Tylose MH300 methyl-2-hydroxyethylcellulose

The same reaction as in 1.11.7 was carried out, using however only 0.35ml of the 2 wt % solution of HPMC (4-6) in Millipore water (molarity ofthe reaction: 2.86 M). The result is compiled below:

Reaction Ex. No. Cellulose derivative Temperature time Yield 1.11.17HPMC (4-6 cps) 50° C. 90 sec 90%

2. Suzuki Reactions General Procedure for Suzuki Reactions Using BoronicAcids

A 5 mL microwave vial was charged with the aryl halide (1.0 equiv.), theboronic acid (1.0-2.10 equiv.) and PdCl₂(dtbpf) (0.02 equiv.). After theaddition of HPMC-solution (40-60 cps, 2 wt % in Millipore water, 3.0 mL)and triethylamine (3.0 equiv.) the reaction mixture was vigorouslystirred (1200 rpm) at the defined temperature until LCMS or TLC showedfull conversion of the aryl halide. The mixture was diluted with EtOAc(5 mL) followed by the addition of a saturated aqueous solution ofsodium sulfate (4 mL). After 5 min of stirring (200 rpm) theprecipitated solids were filtered off and washed with EtOAc (3×15 mL)).After extraction, the organic layer was dried over sodium sulfate. Thecrude product was purified by flash chromatography on silica gel.

2.1 Preparation of 3-(thiophen-3-yl)quinoline

2.1.1) Following the general procedure using 3-bromoquinoline (208 mg,1.00 mmol, 1.0 equiv.), thiophene-3-boronic acid (256 mg, 2.00 mmol,2.00 equiv.), PdCl₂(dtbpf) (13.0 mg, 0.02 mmol, 0.02 equiv.) andtriethylamine (304 mg, 3.00 mmol, 3.0 equiv.) the reaction was allowedto stir for 1 h at room temperature. After column chromatography onsilica gel (0-30% ethyl acetate-cyclohexane) the product was obtained asa white solid (199 mg, 0.94 mmol, 94%).

2.1.2) Following the general procedure using 3-bromoquinoline (219 mg,1.05 mmol, 1.0 equiv.), thiophene-3-boronic acid (269 mg, 2.11 mmol,2.00 equiv.), PdCl₂(dtbpf) (13.7 mg, 0.02 mmol, 0.021 equiv.) andtriethylamine (320 mg, 3.16 mmol, 3.0 equiv.) the reaction was allowedto stir for 10 min at 50° C. After column chromatography on silica gel(0-30% ethyl acetate-cyclohexane) the product was obtained as a whitesolid (209 mg, 0.99 mmol, 94%).

ESI-MS: m/z (%): 212.1 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 9.20 (d, J=2.3 Hz, 1H), 8.28 (d,J=2.3, 1H), 8.19-8.04 (m, 1H), 7.90-7.77 (m, 1H), 7.73-7.68 (m, 1H),7.67-7.64 (m, 1H), 7.59-7.54 (m, 1H), 7.54-7.51 (m, 1H), 7.50-7.47 (m,1H).

2.2 Preparation of 4,6-bis(4-(trifluoromethyl)phenyl)pyrimidine

Following the general procedure using 4,6-dichloropyrimidine (149 mg,1.00 mmol, 1.0 equiv.), 4-(trifluoromethyl)phenylboronic acid (399 mg,2.10 mmol, 2.10 equiv.), PdCl₂(dtbpf) (13.0 mg, 0.02 mmol, 0.02 equiv.)and triethylamine (304 mg, 3.00 mmol, 3.0 equiv.) the reaction wasallowed to stir for 1 h at 50° C. After column chromatography on silicagel (0-30% ethyl acetate-cyclohexane) the product was obtained as awhite solid (345 mg, 0.94 mmol, 94%).

ESI-MS: m/z (%): 369.2 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 9.36 (s, 1H), 8.26 (d, J=8.2 Hz, 4H),8.13 (s, 1H), 7.79 (d, J=8.4 Hz, 4H).

General Procedure for Suzuki Reactions Using Boronic Acid Mida Esters

A 5 mL microwave vial was charged with the boronic acid mida ester (1.0equiv.), the aryl halide (1.0 equiv.) and PdCl₂(dtbpf) (0.02 equiv.).After the addition of HPMC-solution (40-60 cps, 2 wt % in Milliporewater, 1.5 mL) and triethylamine (152 mg, 1.50 mmol, 3.0 equiv.) thereaction mixture was vigorously stirred (1200 rpm) at room temperatureuntil LCMS or TLC showed full conversion of the aryl halide. The mixturewas diluted with EtOAc (3 mL) followed by the addition of a saturatedaqueous solution of sodium sulfate (4 mL). After 5-15 min of stirring(200 rpm) the mixture was filtered through a plug of silica which wasthen washed with EtOAc (3×15 mL). After extraction, the organic layerwas dried over sodium sulfate. The solvent was removed to obtain theproduct.

2.3 Preparation of 5-(benzofuran-2-yl)pyrimidine

Following the general procedure using 2-benzofuranylboronic acid midaester (137 mg, 0.50 mmol, 1.0 equiv.), 5-bromopyrimidine (79 mg, 0.50mmol, 1.0 equiv.), PdCl₂(dtbpf) (6.5 mg, 0.01 mmol, 0.02 equiv.) andtriethylamine (152 mg, 1.50 mmol, 3.0 equiv.) the reaction was allowedto stir for 6 h at room temperature. The product was obtained as a whitesolid (88 mg, 0.45 mmol, 90%).

ESI-MS: m/z (%): 197.3 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 9.25-9.12 (m, 3H), 7.67-7.63 (m, 1H),7.60-7.56 (m, 1H), 7.40-7.35 (m, 1H), 7.32-7.28 (m, 1H), 7.22 (s, 1H).

2.4 Preparation of 4-(benzofuran-3-yl)aniline

Following the general procedure using 2-benzofuranylboronic acid midaester (137 mg, 0.50 mmol, 1.0 equiv.), 4-bromoaniline (86 mg, 0.50 mmol,1.0 equiv.), PdCl₂(dtbpf) (6.5 mg, 0.01 mmol, 0.02 equiv.) andtriethylamine (152 mg, 1.50 mmol, 3.0 equiv.) the reaction was allowedto stir for 14 h at room temperature. The product was obtained as ayellow solid (101 mg, 0.48 mmol, 96%).

ESI-MS: m/z (%): 210.2 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.72-7.64 (m, 2H), 7.57-7.45 (m, 2H),7.25-7.14 (m, 2H), 6.87-6.79 (m, 1H), 6.79-6.71 (m, 2H), 3.84 (s, 2H).

3. Sonogashira Reactions General Procedure for Sonogashira Reactions

Under an argon atmosphere, an aryl halide (1.00 mmol),bis(acetonitrile)palladium(II) dichloride (0.01 mmol) anddicyclohexyl(2′,4′,6′-triisopropyl-[1,1′biphenyl]-2-yl)phosphine (0.013mmol) were weighed into a 5 mL microwave vial containing a magnetic stirbar and Teflon-lined septum. Aqueous oligosaccharide solution (3 ml of 2wt % HPMC, 40-60 cps, in degassed Millipore water) and subsequently analkyne (1.00 mmol) and a base (2.00 mmol) were added. The mixture wasstirred vigorously at room temperature for the indicated time. To thereaction mixture was added ethyl acetate and saturated aqueous sodiumsulfate solution. The solids were filtered off and the aqueous phase wasextracted 4× with ethyl acetate. The combined organic extracts werecombined and concentrated in vacuo. The crude product was purified byflash chromatography on silica gel.

3.1 Preparation of 2-methoxy-4-(phenylethynyl)benzonitrile

3.1.1) Following the general procedure using4-bromo-2-methoxybenzonitrile (212 mg, 1.00 mmol), triethylamine (0.28ml, 2.00 mmol) and phenylacetylene (110 μg, 1.00 mmol) the reaction wasallowed to stir overnight at room temperature. After columnchromatography (0-35% ethyl acetate-cyclohexane), the product wasobtained as a clear oil (186 mg, 80%; 91% purity).

3.1.2) Following the general procedure using4-bromo-2-methoxybenzonitrile (212 mg, 1.00 mmol), cesium carbonate (652mg, 2.00 mmol) and phenylacetylene (110 μg, 1.00 mmol) the reaction wasallowed to stir overnight at room temperature. After columnchromatography (0-35% ethyl acetate-cyclohexane), the product wasobtained as a clear oil (210 mg, 90%, 79% purity).

ESI-MS: m/z (%): 234.10 (100, [M+H]⁺).

¹H NMR (600 MHz, d₆-DMSO): δ [ppm]: 7.79 (d, J=7.9 Hz, 1H), 7.65-7.58(m, 2H), 7.52-7.44 (m, 3H), 7.43 (d, J=1.3 Hz, 1H), 7.27 (dd, J=7.9, 1.4Hz, 1H), 3.97 (s, 3H).

4. Heck Couplings General Procedure for Heck Couplings

Under an argon atmosphere, Pd(t-Bu₃)P₂ (5.1 mg, 0.010 mmol) and an arylhalide (0.50 mmol) were weighed into a 5 mL microwave vial containing amagnetic stir bar and Teflon-lined septum. An acrylate (1.00 mmol)followed by the aqueous oligosaccharide solution (1.5 ml of 2 wt % HPMC,40-60 cps, in degassed Millipore water) were added. Triethylamine (0.21ml, 1.50 mmol) was then added via syringe. The mixture was stirredvigorously for the indicated time at the indicated temperature. To thereaction mixture was added ethyl acetate (4 ml) and subsequently asaturated aqueous sodium sulfate solution (1.5 ml). The solids werefiltered off and the solid was washed 3× with ethyl acetate. The aqueousphase was extracted once with ethyl acetate. The organic extracts werecombined and concentrated in vacuo. The crude product was purified byflash chromatography on silica gel.

4.1 Preparation of (E)-t-butyl 3-(4-methoxyphenyl)acrylate

4.1.1) Following the general procedure using 1-iodo-4-methoxybenzene(117 mg, 0.50 mmol) and t-butyl acrylate (128 mg, 1.00 mmol) thereaction was allowed to stir for 4 h at room temperature. After columnchromatography (0-30% ethyl acetate-heptane), the product was obtainedas a clear oil (80 mg, 65%).

4.1.2) Following the general procedure using 1-iodo-4-methoxybenzene(117 mg, 0.50 mmol) and t-butyl acrylate (128 mg, 1.00 mmol) thereaction was allowed to stir for 1 h at 50° C. After columnchromatography (0-30% ethyl acetate-heptane), the product was obtainedas a clear oil (98 mg, 81%).

ESI-MS: m/z (%): 179.10 (100, [M+H-t-Bu]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.55 (d, J=16.1 Hz, 1H), 7.45 (d,J=8.6 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 6.25 (d, J=16.1 Hz, 1H), 3.85 (s,3H), 1.55 (s, 9H).

4.2 Preparation of t-butyl Cinnamate

4.2.1) Following the general procedure using bromobenzene (79 mg, 0.50mmol) and t-butyl acrylate (128 mg, 1.00 mmol) the reaction was allowedto stir for 72 h at room temperature. After column chromatography (0-30%ethyl acetate-heptane), the product was obtained as a pale oil (80 mg,40%).

4.2.2) Following the general procedure using bromobenzene (79 mg, 0.50mmol) and t-butyl acrylate (128 mg, 1.00 mmol) the reaction was allowedto stir for 4 h at 50° C. (the conversion was however already completedafter 3 h, as indicated by LC-MS). After column chromatography (0-30%ethyl acetate-heptane), the product was obtained as a clear oil (93 mg,88%).

ESI-MS: m/z (%): 149.10 (100, [M+H-t-Bu]⁺).

¹H NMR (600 MHz, CDCl₃): a [ppm]: 7.60 (d, J=16.1 Hz, 1H), 7.55 (m, 2H),7.35 (m, 3H), 6.35 (d, J=16.1 Hz, 1H), 1.55 (s, 9H).

5. C—H-Activation Reactions General Procedure for C—H-ActivationReactions

Urea (1.0 equiv.), aryl halide (2.0 equiv.), AgOAc (2.0 equiv.), andPd(OAc)₂ (0.1 equiv.) were sequentially added in air to a microwavereaction tube equipped with a stir bar and a septum. HPMC solution (4-6cps) in Millipore water (0.25M, 2 wt %), and 48 wt % HBF₄ solution (5equiv.) were added by syringe and vigorously stirred at room temperaturefor 72 h (1200 rpm). EtOAc (3 mL) was added and the mixture was stirredfor 15 min at room temperature. A sat. aq. sol. of Na₂SO₄ (3 mL) wasadded and the mixture was stirred for an additional 15 min. The layerswere separated and the aqueous layer was extracted with EtOAc (3×10 mL).The organic layers were combined and washed with water and brine andthen dried over Na₂SO₄. Concentration of the organic layer afforded thecrude material. The clean product was obtained after flashchromatography on silica gel.

5.1 Preparation of 3-(4′-methoxy-[1,1′-biphenyl]-2-yl)-1,1-dimethylurea

Following the general procedure using 1,1-Dimethyl-3-phenylurea (100 mg,0.61 mmol, 1.0 equiv.), 4-iodoanisole (285 mg, 1.22 mmol, 2.0 equiv.),AgOAc (203 mg, 1.22 mmol, 2.0 equiv.), Pd(OAc)₂ (14 mg, 0.06 mmol, 0.1equiv.), HPMC solution (2.4 mL, 2 wt %), and 48 wt % HBF₄ solution (0.38mL, 3.04 mmol, 5 equiv.) the reaction was allowed to stir for 72 h atroom temperature. After chromatography on silica gel (25-50% EtOAc/Hept)the pure product was obtained as an orange solid (114 mg, 0.42 mmol,69%, 76% brsm).

APCI-MS: m/z (%): 271.2 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 8.17 (d, J=8.3 Hz, 1H), 7.39-7.28 (m,3H), 7.17 (dd, J=7.6, 1.6 Hz, 1H), 7.05 (td, J=7.6, 1.2 Hz, 1H),7.04-6.93 (m, 2H), 6.52 (s, 1H), 3.86 (s, 3H), 2.82 (s, 6H).

6. Stile Couplings General Procedure for Stille Couplings

To Pd(P^(t)Bu₃)₂ (0.02 equiv.), 1,4-diazabicyclo[2.2.2]octane (3.0equiv.) and NaCl (1.0 equiv.) under an argon atmosphere was given a 2 wt% solution of HPMC (4-6 cps) in Millipore water (0.5 M), followed by thearyl halide (1.0 equiv.) and the stannyl reagent (1.1 equiv.). Themixture was stirred vigorously under an argon atmosphere at theindicated temperature for the indicated time. The reaction was quenchedwith trimethylamine (0.5 mL) and diluted with EtOAc (1 mL). After theaddition of a saturated Na₂SO₄-solution (1 mL) the mixture was extractedwith EtOAc (2×10 mL). The clean product was obtained after flashchromatography on silica gel.

6.1 Preparation of (Z)-2-(2-ethoxyvinyl)-1,3-dimethylbenzene

6.1.1) Following the general procedure using 2-bromo-m-xylene (92 mg,0.5 mmol, 1.0 equiv), (Z)-1-ethoxy-2-(tributylstannyl)ethene (197 mg,0.55 mml, 1.1 equiv), Pd(P^(t)Bu₃)₂ (5.0 mg, 0.01 mmol, 0.02 equiv.),1,4-diazabicyclo[2.2.2]octane (167 mg, 1.5 mmol, 3.0 equiv.) and NaCl(29 mg, 0.5 mmol, 1.0 equiv.) the reaction was allowed to stirvigorously under an argon atmosphere for 48 h at room temperature. Aftercolumn chromatography (EtOAc/hexanes), the product was obtained (68 mg,0.38 mmol, 78%)

6.1.2) Following the general procedure using 2-bromo-m-xylene (92 mg,0.5 mmol, 1.0 equiv), (Z)-1-ethoxy-2-(tributylstannyl)ethene (197 mg,0.55 mmol, 1.1 equiv), Pd(P^(t)Bu₃)₂ (5.0 mg, 0.01 mmol, 0.02 equiv.),1,4-diazabicyclo[2.2.2]octane (167 mg, 1.5 mmol, 3.0 equiv.) and NaCl(29 mg, 0.5 mmol, 1.0 equiv.) the reaction was allowed to stirvigorously (1200 rpm) under an argon atmosphere for 2 h at 50° C. andthen for 24 h at room temperature. After column chromatography(EtOAc/hexanes), the product was obtained (45 mg, 0.26 mmol, 52%)

ESI-MS: m/z (%): 177.2 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.10-6.98 (m, 3H), 6.20 (d, J=6.9 Hz,1H), 5.20 (d. J=6.9 Hz, 1H), 3.86 (q, J=7.1 Hz, 2H), 2.27 (s, 6H), 1.24(t, J=7.1 Hz, 3H).

7. Cross Metathesis General Procedure for Cross Metathesis

Under an argon atmosphere, Grubbs second-generation catalyst (3.4 mg,0.004 mmol) was weighed into a 5 mL microwave vial containing a magneticstir bar and Teflon-lined septum. The alkene (0.50 mmol) and acrylate(1.00 mmol) were added sequentially into the vial, followed by additionof the aqueous oligosaccharide solution (2 ml of 2 wt % HPMC, 40-60 cps,in degassed Millipore water). The mixture was stirred vigorously at roomtemperature for the indicated time. To the reaction mixture was addedethyl acetate and saturated aqueous sodium sulfate solution. The solidswere filtered off and the aqueous phase was extracted 3× with ethylacetate. The combined organic extracts were combined and concentrated invacuo. The crude product was purified by flash chromatography on silicagel.

7.1 Preparation of (E)-tert-butyl 4-(4-methoxyphenyl)but-2-enoate

7.1.1) Following the general procedure using 4-allylanisole (74 mg, 0.50mmol) and tert-butyl acrylate (128 mg, 1.00 mmol) the reaction wasallowed to stir overnight at room temperature. After columnchromatography (0-10% ethyl acetate-dichloromethane), the product wasobtained as a clear oil (73 mg, 59%).

7.1.2) Following the general procedure using 4-allylanisole (74 mg, 0.50mmol), tert-butyl acrylate (128 mg, 1.00 mmol) and additionally citricacid (9.6 mg, 0.005 mmol) was added and the reaction was allowed to stirovernight at room temperature. After column chromatography (0-20% ethylacetate-dichloromethane), the product was obtained as a clear oil (96mg, 77%).

ESI-MS: m/z (%): 193.10 (100, [M+H-^(t)Bu]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.11-7.07 (m, 2H), 7.00-6.94 (m, 1H),6.87-6.83 (m, 2H), 5.73-5.68 (m, 1H), 3.80 (s, 3H), 3.45-3.41 (m, 2H),1.46 (s, 9H).

8. Rh-Catalyzed 1,4-Additions General Procedure for Rh-Catalyzed1,4-Additions

Under an argon atmosphere, an aryl boronic acid (1.84 mmol), potassiumcarbonate (254 mg, 1.84 mmol) and hydroxyl(cyclootadiene)rhodium(I)dimer(21 mg, 0.046 mmol) were weighed into a 5 mL microwave vial containing amagnetic stir bar, Teflon-lined septum and the aqueous oligosaccharidesolution (3 ml of 2 wt % HPMC, 40-60 cps, in degassed Millipore water).To the reaction mixture was added an α,β-unsaturated ethyl ester (0.92mmol) and stirred vigorously at the indicated temperature for theindicated time. To the reaction mixture was added saturated aqueoussodium sulfate solution and ethyl acetate. The aqueous phase wasextracted 4× with ethyl acetate. The combined organic extracts werecombined and concentrated in vacuo. The crude product was purified byflash chromatography on silica gel.

8.1 Preparation of 4-methyl-3,4-dihydroquinolin-2(1H)-one

Following the general procedure using (2-aminophenyl)boronic acid (252mg, 1.84 mmol) and (E-)ethyl but-2-enoate (105 mg, 0.92 mmol) thereaction was allowed to stir for 5 h at 50° C. After columnchromatography (0-30% ethyl acetate-cyclohexane), the product wasobtained (147 mg, 99%).

ESI-MS: m/z (%): 162.20 (100, [M+H]⁺).

¹H NMR (600 MHz, d₆-DMSO): δ [ppm]: 10.09 (s, 1H), 7.19 (ddd, J=7.5,1.5, 0.8 Hz, 1H), 7.13 (td, J=7.6, 1.5 Hz, 1H), 6.94 (td, J=7.5, 1.2 Hz,1H), 6.85 (dd, J=7.9, 1.2 Hz, 1H), 3.04 (q, J=6.9 Hz, 1H), 2.58 (dd,J=15.9, 5.9 Hz, 1H), 2.23 (dd, J=15.9, 7.0 Hz, 1H), 1.17 (d, J=7.0 Hz,3H).

9. Gold-Catalyzed Cyclizations General Procedure for Gold-CatalyzedCyclizations

Under an argon atmosphere the diol (1.0 equiv.) was dissolved in a 2 wt% solution of HPMC (4-6 cps) in Millipore water (0.8 mL). After theaddition of gold(III) bromide (0.025 equiv.) and silver triflate (0.025equiv.) the mixture was stirred under an argon atmosphere at roomtemperature (1200 rpm) for 4 h. The mixture was diluted with EtOAc (3mL) and filtered through a pad of silica which was washed with EtOAc(3×10 ml). The clean product was obtained after flash chromatography onsilica gel.

9.1 Preparation of 2,3-dimethyl-5-phenylfuran

Following the general procedure using3-methyl-5-phenylpent-4-yne-2,3-diol (76 mg, 0.40 mmol, 1.0 equiv.),AuBr₃ (4.4 mg, 0.01 mmol, 0.025 equiv.) and AgOTf (2.6 mg, 0.01 mmol,0.025 equiv.) the reaction was allowed to stir for 4 h at roomtemperature under an argon atmosphere. After column chromatography(cyclohexane), the product was obtained as a pale orange oil (49 mg,0.29 mmol, 71%).

ESI-MS: m/z (%): 173.3 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.63-7.56 (m, 2H), 7.37-7.28 (m, 2H),7.23-7.14 (m, 1H), 6.43 (s, 1H), 2.26 (s, 3H), 1.97 (s, 3H).

10. Miyaura Borylations General Procedure for Miyaura Borylations

To Pd(P^(t)Bu₃)₂ (0.03 equiv.), B₂pin₂ (1.1 equiv.) and KOAc (3.0 equiv)under an argon atmosphere was given a 2 wt % solution of HPMC (4-6 cps)in Millipore water (1.0 mL). After 10 min of vigorous stirring, the arylbromide (1.0 equiv.) was added, followed by an additional amount of a 2wt % solution of HPMC (4-6 cps) in Millipore water (1.0 mL). The mixturewas stirred vigorously under an argon atmosphere for the indicated timeat the indicated temperature. The reaction was diluted with a saturatedNa₂SO₄-solution (2 mL), stirred for 3 min and then extracted with EtOAc(3×10 mL). The clean product was obtained after flash chromatography onsilica gel.

10.1 Preparation of2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Following the general procedure using 4-bromoanisole (94 mg, 0.5 mmol,1.0 equiv.), bis(pinacolato)diboron (140 mg, 0.55 mmol, 1.1 equiv.),bis(tri-tert-butylphosphine)palladium(0) (7.7 mg, 0.015 mmol, 0.03equiv.) and KOAc (147 mg, 1.5 mmol, 3.0 equiv.) the reaction was allowedto stir vigorously for 2 h at room temperature. After columnchromatography (EtOAc/hexanes), the product was obtained (94 mg, 0.40mmol, 80%).

ESI-MS: m/z (%): 235.1 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.77-7.73 (m, 2H), 6.91-6.87 (m, 2H),3.82 (s, 3H), 1.33 (s, 12H).

10.2 Preparation of2-(2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Following the general procedure using 2-bromo-m-xylene (93 mg, 0.5 mmol,1.0 equiv.), bis(pinacolato)diboron (140 mg, 0.55 mmol, 1.1 equiv.),bis(tri-tert-butylphosphine)palladium(0) (15 mg, 0.03 mmol, 0.06 equiv.)and KOAc (147 mg, 1.5 mmol, 3.0 equiv.) the reaction was allowed to stirvigorously (1200 rpm) for 7 h at 50° C. and then for 24 h at roomtemperature. After column chromatography (EtOAc/hexanes), the productwas obtained (85 mg, 0.37 mmol, 73%).

ESI-MS: m/z (%): 233.1 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.15-7.08 (m, 1H), 6.97-6.89 (m, 2H),2.39 (s, 6H), 1.39 (s, 12H).

11. Wittig Reactions General Procedure for Wittig Reactions

A 5 mL microwave vial was charged with the carbonyl compound (1.0equiv.) and the Wittig reagent (1.5 equiv.). After the addition ofHPMC-solution (40-60 cps, 2 wt % in Millipore water, 2.0 mL) thereaction mixture was vigorously stirred (1200 rpm) at the indicatedtemperature until LCMS or TLC showed full conversion of the carbonylcompound. The mixture was diluted with EtOAc (3 mL) followed by theaddition of a saturated aqueous solution of sodium sulfate (4 mL). After5-15 min of stirring (200 rpm) the mixture was filtered through a plugof silica which was then washed with EtOAc (3×15 mL). The combinedorganic layers were dried over sodium sulfate. The crude product waspurified by flash chromatography on silica gel.

11.1 Preparation of (E)-methyl 3-(4-methoxyphenyl)acrylate

Following the general procedure using 4-methoxybenzaldehyde (68 mg, 0.50mmol, 1.0 equiv.) and methyl (triphenylphosphoranylidene)acetate (251mg, 0.75 mmol, 1.5 equiv.) the reaction was allowed to stir for 30 minat 50° C. After column chromatography on silica gel (5-30% ethylacetate-cyclohexane) the product was obtained as a white solid (90 mg,0.47 mmol, 94%). (E/Z=14/1)

ESI-MS: m/z (%): 193.2 (80, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃) (of the E configurated product): δ [ppm]: 7.66(d, J=16.0 Hz, 1H), 7.54-7.42 (m, 2H), 6.97-6.86 (m, 2H), 6.32 (d,J=16.0 Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H).

12. Diels-Alder Reactions General Procedure for Diels-Alder Reactions

A 5 mL microwave vial was charged with the dienophile (1.0 equiv.) andthe diene (1.0-1.5 equiv.). After the addition of HPMC-solution (40-60cps, 2 wt % in Millipore water, 1.0 mL) the reaction mixture wasvigorously stirred (1200 rpm) at the indicated temperature until LCMS orTLC showed full conversion of the dienophile. The mixture was dilutedwith EtOAc (3 mL) followed by the addition of a saturated aqueoussolution of sodium sulfate (4 mL). After 5-15 min of stirring (200 rpm)the mixture was filtered through a plug of silica which was then washedwith EtOAc (3×15 mL). After phase separation, the organic layer wasdried over sodium sulfate. The clean product was obtained after flashchromatography on silica gel.

12.1 Preparation of(7-methyl-1,3-dioxo-2-propyl-2,3,3a,4,7,7a-hexahydro-1H-iso-indol-4-yl)methylAcetate

Following the general procedure using 1-propyl-1H-pyrrole-2,5-dione (139mg, 1.00 mmol, 1.0 equiv.) and (2E,4E)-hexa-2,4-dien-1-yl acetate (154mg, 1.10 mmol, 1.1 equiv.) the reaction was allowed to stir for 4 h at50° C. After column chromatography on silica gel (0-30% ethylacetate-cyclohexane) the product was obtained as a colourless oil (201mg, 0.72 mmol, 72%)

ESI-MS: m/z (%): 280.3 (80, [M+H]⁺), 581.3 (100, [2M+H]⁺).

¹H NMR (600 MHz, CDCl₃): 5.82-5.69 (m, 2H), 4.74-4.60 (m, 1H), 4.55-4.46(m, 1H), 3.44-3.32 (m, 2H), 3.28-3.18 (m, 1H), 3.09-2.99 (m, 1H),2.68-2.55 (m, 1H), 2.49-2.38 (m, 1H), 2.09 (s, 3H), 1.54-1.47 (m, 2H),1.45 (d, J=7.4 Hz, 3H), 0.83 (t, J=7.5 Hz, 3H).

13. Baylis-Hillman Reactions General Procedure for Baylis-HillmanReactions

To the aldehyde (1.0 equiv.) in a 2 wt % solution of HPMC (4-6 cps) inMillipore water (0.3 M) was given the alkene (7.0 equiv.) and1,4-diazabicyclo[2.2.2]octane (0.2 equiv.). The mixture was stirred in aspetum-closed 5 mL-microwave vial for the indicated time at roomtemperature. The mixture was diluted with EtOAc (3 mL) and then with asat. solution of Na₂SO₄ (3 mL). After stirring for 3 min the mixture wasfiltered through a pad of silica which was washed with EtOAc (3×15 mL).The clean product was obtained after flash chromatography on silica gel.

13.1 Preparation of 2-((4-chlorophenyl)(hydroxy)methyl)acrylonitrile

Following the general procedure using 4-chlorobenzaldehyde (141 mg, 1.0mmol, 1.0 equiv.), acrylonitrile (371 mg, 7.0 mmol, 7.0 equiv.) and1,4-diazabicyclo[2.2.2]octane (22 mg, 0.2 mmol, 0.2 equiv.) the reactionwas allowed to stir for 23 h at room temperature. After columnchromatography (ethyl acetate/cyclohexane), the product was obtained asa white solid (148 mg, 0.76 mmol, 76%).

APCI-MS: m/z (%): 194.0 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.38-7.32 (m, 2H), 7.32-7.27 (m, 2H),6.13-6.04 (m, 1H), 6.04-5.96 (m, 1H), 5.24 (s, 1H), 3.07 (s_(br), 1H).

14. Amide Bond Formations General Procedure for Amide Bond FormationsUsing 1-hydroxybenzotriazol (HOBT) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimid Hydrochloride (EDCHydrochloride)

Under an argon atmosphere, an acid (1.00 mmol) was weighed into a 5 mLmicrowave vial containing a magnetic stir bar and a Teflon-lined septum.Subsequently EDC hydrochloride (240 mg, 1.25 mmol), HOBT (184 mg, 1.20mmol) and an aqueous oligosaccharide solution (3 ml of 2 wt % HPMC,40-60 cps, in degassed Millipore water) were added and the reactionmixture was stirred vigorously at the indicated temperature. After 2 minan amine (1.10 mmol) was added and stirring was continued for theindicated time. The reaction mixture was adjusted to an alkaline pH byadding 1 ml of a 2N aqueous sodium hydroxide solution and extracted 4×with ethyl acetate. The combined organic extracts were dried withmagnesium sulfate and after filtration concentrated in vacuo. The crudeproduct was purified by flash chromatography on silica gel.

14.1 Preparation of N-(2-(diethylamino)ethyl)-4-nitrobenzamide

Following the general procedure using 4-nitrobenzoic acid (167 mg, 1.00mmol) and N,N-diethylethylenediamine (128 mg, 1.10 mmol) the reactionwas allowed to stir for 20 min at room temperature (the conversion washowever already completed after 2 min, as indicated by LC-MS). Aftercolumn chromatography (0-10% methanol-dichloromethane), the product wasobtained (220 mg, 83%).

ESI-MS: m/z (%): 266.20 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 8.31-8.24 (m, 2H), 8.02-7.97 (m, 2H),3.63-3.57 (m, 2H), 2.83 (s, 2H), 2.73 (d, J=12.3 Hz, 4H), 1.17-1.10 (m,6H).

General Procedure for Amide Bond Formations Using(1-cyano-2-ethoxy-2-oxoethyliden-aminooxy)dimethylamino-morpholino-carbenium-hexafluorophosphat(COMU)

Under an argon atmosphere, an acid (1.10 mmol) was weighed into a 5 mLmicrowave vial containing a magnetic stir bar and a Teflon-lined septum.The aqueous oligosaccharide solution (2 wt % HPMC, 40-60 cps, indegassed Millipore water) was added, followed by 2,6-dimethylpyridine(332 mg, 3.1 mmol), and the reaction mixture was vigorously stirred atroom temperature for 5 min. An amine (1.00 mmol) followed by1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium-hexafluorophosphat(COMU) (471 mg, 1.10 mmol) were added to the reaction mixture andstirring was continued for the indicated time at the indicatedtemperature. The reaction mixture was diluted with ethyl acetate andsaturated aqueous sodium sulfate solution. The solids were filtered andwashed 4× with ethyl acetate. The combined organic extracts were treated3× with aqueous 1 N hydrochloride solution and subsequently 4× withsaturated aqueous sodium carbonate solution. The organic phase was driedwith magnesium sulfate, filtered and concentrated in vacuo. The crudeproduct was purified by flash chromatography on silica gel.

14.2 Preparation of (R)-ethyl2-(((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanoyl)oxy-4-methylpentanoate

Following the general procedure using Fmoc-Val-OH (373 mg, 1.10 mmol),L-Leucine ethyl ester hydrochloride (196 mg, 1.00 mmol) and1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium-hexafluorophosphat(COMU) (471 mg, 1.10 mmol) in 1.25 ml of aqueous oligosaccharidesolution (2 wt % HPMC, 40-60 cps, in degassed Millipore water), thereaction was allowed to stir overnight at room temperature. After columnchromatography (0-10% methanol-dichloromethane), the product wasobtained (430 mg, 89%).

ESI-MS: m/z (%): 481.20 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.77 (dq, J=7.7, 1.2 Hz, 2H), 7.60 (d,J=7.5 Hz, 2H), 7.40 (tdd, J=7.4, 2.2, 1.0 Hz, 2H), 7.32 (tdd, J=7.5,2.4, 1.1 Hz, 2H), 6.06 (d, J=8.2 Hz, 1H), 5.40 (d, J=9.0 Hz, 1H),4.64-4.57 (m, 1H), 4.42 (dd, J=10.6, 7.4 Hz, 1H), 4.36 (dd, J=10.6, 7.1Hz, 1H), 4.26-4.15 (m, 3H), 4.00 (dd, J=8.9, 6.3 Hz, 1H), 2.13 (dt,J=13.4, 6.7 Hz, 1H), 1.65 (s, 2H), 1.55 (s, 1H), 1.28 (t, J=7.2 Hz, 3H),1.01-0.90 (m, 12H).

14.3 Preparation of N-3,4-dimethoxyphenethyl)-2-phenylacetamide

14.3.1) Following the general procedure using phenyl acetic acid (150mg, 1.10 mmol), 3,4-dimethoxyphenethylamine (181 mg, 1.00 mmol) and COMU(471 mg, 1.10 mmol) in 2 ml of aqueous oligosaccharide solution (2 wt %HPMC, 40-60 cps, in degassed Millipore water), the reaction was allowedto stir for 30 min. at room temperature. After column chromatography(50-100% ethyl acetate-heptane), the product was obtained as a clear oil(243 mg, 78%).

14.3.2) Following the general procedure using phenyl acetic acid (150mg, 1.10 mmol), 3,4-dimethoxyphenethylamine (181 mg, 1.00 mmol) and 2 mlof aqueous oligosaccharide solution (2 wt % HPMC, 40-60 cps, in degassedwater), the reaction was allowed to stir for 20 min. at 50° C. Aftercolumn chromatography (50-100% ethyl acetate-heptane), the product wasobtained as a clear oil (258 mg, 82%).

14.3.3) Following the general procedure using phenyl acetic acid (150mg, 1.10 mmol), 3,4-dimethoxyphenethylamine (181 mg, 1.00 mmol) and COMU(471 mg, 1.10 mmol) in 0.35 ml of aqueous oligosaccharide solution (2 wt% HPMC, 40-60 cps, in degassed Millipore water), the reaction wasallowed to stir for 20 min. at room temperature. LC-MS and TLC indicatedhowever that the reaction was already completed after 1 min. Aftercolumn chromatography (50-100% ethyl acetate-heptane), the product wasobtained as a clear oil (251 mg, 81%, 97% purity).

14.3.4) Following the general procedure using phenyl acetic acid (150mg, 1.10 mmol), 3,4-dimethoxyphenethylamine (181 mg, 1.00 mmol) and COMU(471 mg, 1.10 mmol) in 0.35 ml of aqueous oligosaccharide solution (2 wt% HPMC, 40-60 cps, in degassed Millipore water), the reaction wasallowed to stir for 15 min. at 50° C. LC-MS and TLC indicated howeverthat the reaction was already completed after 1 min. After columnchromatography (50-100% ethyl acetate-heptane), the product was obtainedas a clear oil (255 mg, 81%, 95% purity).

ESI-MS: m/z (%): 300.10 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.35-7.25 (m, 3H), 7.15 (m, 2H), 6.70(m, 1H), 6.60 (m, 1H), 6.55 (m, 1H), 5.35 (s_(br), 1H), 3.85 (s, 3H),3.80 (s, 3H), 3.55 (s, 2H), 3.45 (m, 2H), 2.70 (t, 3H).

General Procedure for Sulfonylations

Under an argon atmosphere, a base (2.97 mmol) and the aqueousoligosaccharide solution (2 wt % HPMC, in degassed Millipore water) wereweighed into a 5 mL microwave vial containing a magnetic stir bar and aTeflon-lined septum. An amine (0.99 mmol) and subsequently a sulfonylchloride (1.98 mmol) were added to the vigorously stirred reactionmixture at room temperature. Stirring was continued for the indicatedtime at the indicated temperature. The reaction mixture was diluted withethyl acetate, the solids were filtered and the aqueous phase wasextracted 3× with ethyl acetate. The combined organic extracts weredried with magnesium sulfate, filtered and concentrated in vacuo. Thecrude product was purified by flash chromatography on silica gel.

14.4 Preparation of 1-(phenylsulfonyl)indoline

14.4.1) Following the general procedure using potassiumtrimethylsilanolate (380 mg, 2.97 mmol), indoline (119 mg, 0.99 mmol),benzenesulfonyl chloride (364 mg, 1.98 mmol) and 3 ml of aqueousoligosaccharide solution (2 wt % HPMC, 40-60 cps, in degassed Milliporewater), the reaction was allowed to stir for 30 min room temperature.After column chromatography (40-100% n-heptane-dichloromethane), theproduct was obtained as a white crystalline material (233 mg, 89%).

14.4.2) Following the general procedure using potassiumtrimethylsilanolate (380 mg, 2.97 mmol), indoline (119 mg, 0.99 mmol),benzenesulfonyl chloride (220 mg, 1.20 mmol) and 3 ml of aqueousoligosaccharide solution (2 wt % HPMC, 4-6 cps, in degassed Milliporewater), the reaction was allowed to stir for 30 min room temperature.LC-MS and TLC indicated that the reaction was already completed after 5min. After column chromatography (40-100% n-heptane-dichloromethane),the product was obtained as a white crystalline material (262 mg, 97%,96% purity).

ESI-MS: m/z (%): 260.20 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.80 (m, 2H), 7.65 (m, 1H), 7.55 (m,1H), 7.45 (m, 2H), 7.20 (m, 1H), 7.10 (m, 1H), 7.00 (m, 1H), 3.95 (m,2H), 2.90 (m, 2H).

14.5 Preparation of N-(4-fluorophenyl)-4-methylbenzenesulfonamide

Following the general procedure using triethylamine (209 μl, 1.50 mmol),4-fluoroaniline (112 mg, 1.00 mmol), 4-methylbenzene-1-sulfonyl chloride(233 mg, 1.20 mmol) and 3 ml of aqueous oligosaccharide solution (2 wt %HPMC, 4-6 cps, in degassed Millipore water), the reaction was allowed tostir for 20 min room temperature. After column chromatography (0-50%n-heptane-ethyl acetate), the product was obtained as a clear oil (222mg, 80%).

ESI-MS: m/z (%): 266.20 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.60 (m, 2H), 7.20 (m, 2H), 7.00 (m,2H), 6.95 (m, 2H), 6.30 (s_(br), 1H), 2.40 (s, 3H).

15. Nucleophilic Aromatic Substitutions General Procedure forNucleophilic Aromatic Substitutions

To the aryl halide (1.0 equiv.) and the nucleophile (1.0-1.1 equiv.) ina 5 mL microwave vial was added a 2 wt % solution of HPMC (40-60 cps) inMillipore water (1 mL). After the addition of sodium tert-butoxide (1.1equiv) the mixture was vigorously stirred (1200 rpm) at room temperatureuntil LCMS or TLC showed full conversion of the aryl halide. The mixturewas diluted with EtOAc (3 mL) followed by the addition of a saturatedaqueous solution of sodium sulfate (2 mL). After 5-15 min of stirring(200 rpm) the precipitated solids were filtered off and washed withEtOAc (3×15 mL.). After extraction, the organic layer was dried oversodium sulfate. The crude product was purified by flash chromatographyon silica gel.

15.1 Preparation of2,5-dichloro-N-(3,4-dimethoxyphenethyl)pyrimidin-4-amine

Following the general procedure using 3,4-dimethoxyphenethylamine (90.0mg, 0.50 mmol, 1.0 equiv.), 2,4,5-trichloropyrimidine (91.5 mg, 0.50mmol, 1.0 equiv.) and sodium tert-butoxide (52.8 mg, 0.55 mmol, 1.1equiv) the reaction was allowed to stir for 10 min at room temperature.After column chromatography (0-30% ethyl acetate-cyclohexane), theproduct was obtained as a white solid (140 mg, 0.43 mmol, 86%).

ESI-MS: m/z (%): 328 (100, [M]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.99 (s, 1H), 6.88-6.79 (m, 1H),6.80-6.71 (m, 2H), 5.61 (s_(br), 1H), 3.88 (s, 3H), 3.87 (s, 3H),3.79-3.73 (m, 2H), 2.88 (t, J=6.9 Hz, 2H).

15.2 Preparation of N-benzyl-2-nitroaniline

Following the general procedure using benzylamine (53.6 mg, 0.50 mmol,1.0 equiv.), 1-fluoro-2-nitrobenzene (70.5 mg, 0.50 mmol, 1.0 equiv.)and sodium tert-butoxide (72.1 mg, 0.75 mmol, 1.5 equiv) the reactionwas allowed to stir for 3 h at room temperature. After columnchromatography (0-30% ethyl acetate-cyclohexane), the product wasobtained as a white solid (89 mg, 0.39 mmol, 78%).

ESI-MS: m/z (%): 229.20 (100, [M]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 8.44 (s, 1H), 8.20 (dd, J=8.6, 1.6 Hz,1H), 7.44-7.27 (m, 7H), 6.83-6.79 (m, 1H), 6.69-6.64 (m, 1H), 4.55 (d,J=5.7 Hz, 2H).

15.3 Preparation of naphthalen-2-yl(2-nitrophenyl)sulfane

Following the general procedure using 1-fluoro-2-nitrobenzene (70.5 mg,0.50 mmol, 1.0 equiv.), 2-naphthalenethiol (88.0 mg, 0.55 mmol, 1.1equiv.) and sodium tert-butoxide (52.8 mg, 0.55 mmol, 1.1 equiv) thereaction was allowed to stir for 3 h at room temperature. After columnchromatography (0-30% ethyl acetate-cyclohexane), the product wasobtained as a yellow solid (127 mg, 0.45 mmol, 90%).

ESI-MS: m/z (%): 304.1 (40, [M+Na]⁺), 585.2 (100, [2M+Na]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 8.28-8.21 (m, 1H), 8.20-8.14 (m, 1H),7.95-7.88 (m, 2H), 7.89-7.83 (m, 1H), 7.64-7.54 (m, 2H), 7.54-7.50 (m,1H), 7.32-7.26 (m, 1H), 7.23-7.17 (m, 1H), 6.89 (dd, J=8.3, 1.2 Hz, 1H).

16. Nitro Reduction General Procedure for Nitro Reduction Using Zinc

Under an argon atmosphere, a nitro group-containing compound (0.237mmol) was weighed into a 5 mL microwave vial containing a magnetic stirbar and a Teflon-lined septum. Subsequently zinc dust (155 mg, 2.37mmol), ammonium chloride (25 mg, 0.475 mmol) and the aqueousoligosaccharide solution (2 wt % HPMC, 40-60 cps, in degassed Milliporewater) were added and the reaction mixture was vigorously stirred at theindicated temperature for the indicated time. The reaction mixture wasdiluted with ethyl acetate, the solids were filtered and the aqueousphase was extracted 3× with ethyl acetate. The combined organic extractswere dried with magnesium sulfate, filtered and concentrated in vacuo.The crude product was purified by flash chromatography on silica gel.

16.1 Preparation of 4-amino-N-(2-(diethylamino)ethyl)benzamide

Following the general procedure usingN-(2-diethylamino)ethyl)-4-nitrobenzamide (63 mg, 0.237 mmol), zinc (155mg, 2.37 mmol), ammonium chloride (25 mg, 0.475 mmol) and 1.25 ml ofaqueous oligosaccharide solution (2 wt % HPMC, 40-60 cps, in degassedMillipore water), the reaction was allowed to stir for 2 h at roomtemperature (the conversion was however already completed after 5 min,as indicated by LC-MS). After the work-up the clean product was obtained(46 mg, 82%).

ESI-MS: m/z (%): 236.10 (100, [M+H]⁺).

¹H NMR (600 MHz, d₆-DMSO): δ [ppm]: 7.91 (d, J=6.0 Hz, 1H), 7.56-7.50(m, 2H), 6.56-6.49 (m, 2H), 5.59 (s, 2H), 3.30-3.24 (m, 2H), 2.57-2.51(m, 6H), 0.97 (t, J=7.1 Hz, 6H).

16. Preparation of 3-fluoro-4-methoxyaniline

Following the general procedure using 2-fluoro-4-nitroanisole (171 mg,1.00 mmol), zinc (327 mg, 5.00 mmol), ammonium chloride (64 mg, 1.20mmol) and 2 ml of aqueous oligosaccharide solution (2 wt % HPMC, 40-60cps, in degassed Millipore water), the reaction was allowed to stir for5 min at room temperature. After column chromatography (0-100% ethylacetate-dichloromethane), the product was obtained (110 mg, 78%).

ESI-MS: m/z (%): 142.10 (100, [M+H]⁺).

¹H NMR (600 MHz, d₆-DMSO): δ [ppm]: 6.85-6.81 (m, 1H), 6.41-6.37 (m,1H), 6.31-6.28 (m, 1H), 4.91 (s_(br), 2H), 3.68 (s, 3H).

General Procedure for Hydrogenations of Nitro Groups Using Pd/C

To the nitro compound (1.0 equiv.) was added a 2 wt % solution of HPMC(40-60 cps) in Millipore water (0.5 M) and palladium on carbon (10%,0.05 equiv.). The mixture was stirred vigorously under a hydrogenatmosphere for the indicated time at room temperature. The mixture wasdiluted with EtOAc (3 mL) and a sat. solution of Na₂SO₄ (2 mL),filtered, extracted with EtOAc (3×15 mL) and dried over MgSO₄. The cleanproduct was obtained after flash chromatography on silica gel.

16.3 Preparation of 4-methoxyaniline

Following the general procedure using 4-nitroanisole (600 mg, 3.92 mmol,1.0 equiv.) and palladium on carbon (10%, 208 mg, 0.2 mmol, 0.05 equiv)the reaction was allowed to stir under a hydrogen atmosphere for 18 h atroom temperature. After column chromatography (dichloromethane/ethylacetate), the product was obtained (430 mg, 3.49 mmol, 89%).

ESI-MS: m/z (%): 124.1 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 6.79-6.71 (m, 2H), 6.68-6.63 (m, 2H),3.75 (s, 3H), 3.52 (s_(br), 2H).

17. CuH Reductions of Double Bonds General Procedure for CuH Reductionsof Double Bonds

To Cu(OAc)₂ (0.03 equiv.) and(6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphine)(0.03 equiv.) under argon was given a 2 wt % solution of HPMC (4-6 cps)in Millipore water (0.25 M). After the addition of the alkene (1.0equiv.) the mixture was stirred for 5 min at room temperature.Polymethylhydrosiloxane (0.31 equiv.) was slowly added and the mixturewas stirred under argon for the indicated time at room temperature. Thereaction was quenched with a NH₄F solution and stirred for 2 h at roomtemperature. The mixture was filtered through a short pad of silicawhich was washed with methanol (3×15 ml). The clean product was obtainedafter flash chromatography on silica gel.

17.1 Preparation of ethyl 3-phenylbutanoate

Following the general procedure using ethyl trans-beta-methylcinnamate(95 mg, 0.5 mmol, 1.0 equiv.),(6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethyl-phenyl)phosphine)(10.4 mg, 0.015 mmol, 0.03 equiv.), polymethylhydrosiloxane (294 mg,0.155 mmol, 0.31 equiv.) and Cu(OAc)₂ (2.7 mg, 0.015 mmol, 0.03 equiv.)the reaction was allowed to stir under an argon atmosphere for 24 h atroom temperature. After column chromatography (ethylacetate/cyclohexane), the product was obtained (95 mg, 0.49 mmol, 99%).

APCI-MS: m/z (%): 193.2 (100, [M+H]⁺).

¹H NMR (600 MHz, d₆-DMSO): δ [ppm]: 7.33-7.22 (m, 4H), 7.23-7.13 (m,1H), 4.03-3.91 (m, 2H), 3.21-3.09 (m, 1H), 2.63-2.54 (m, 2H), 1.21 (d,J=7.0 Hz, 3H), 1.09 (t, J=7.1 Hz, 3H).

18. Reductive Amination General Procedure for Reductive Aminations UsingAldehydes

A 5 mL microwave vial was charged with the amine (1.0 equiv.),borane-2-picoline complex (1.2 equiv.) and diphenyl phosphate (0.1equiv.). After the addition of HPMC-solution (40-60 cps, 2 wt % inMillipore water, 1.25 mL) and the aldehyde (1.2 equiv.) the reactionmixture was vigorously stirred at room temperature until LCMS or TLCshowed full conversion of the starting materials. The mixture wasquenched with a saturated solution of sodium hydrogen carbonate in water(1 mL), diluted with EtOAc (3 mL) and stirred for 2 min. After theaddition of a saturated solution of sodium sulfate (2 mL) the phaseswere separated and the aqueous phase was further extracted with EtOAc(3×). The combined organic layers were dried over sodium sulfate. Thecrude product was purified by flash chromatography on silica gel.

18.1 Preparation of N-benzyl-4-methoxyaniline

Following the general procedure using p-anisidine (62.0 mg, 0.50 mmol,1.0 equiv.), borane-2-picoline complex (64.6 mg, 0.60 mmol, 1.2 equiv.),diphenyl phosphate (12.6 mg, 0.05 mmol, 0.1 equiv.) and freshlydistilled benzaldehyde (64.1 mg, 0.60 mmol, 1.2 equiv.) the reaction wasstirred for 2 h at room temperature. After column chromatography onsilica gel (0-100% ethyl acetate-heptane) the product was obtained as acolorless oil (88 mg, 0.41 mmol, 82%).

ESI-MS: m/z (%): 214.1 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.37-7.21 (m, 5H), 6.79-6.71 (m, 2H),6.61-6.51 (m, 2H), 4.23 (s, 2H), 3.75 (s_(br), 1H), 3.69 (s, 3H).

General Procedure for Reductive Aminations Using Ketones

A 5 mL microwave vial was charged with the amine (1.0 equiv.),borane-2-picoline complex (1.2 equiv.) and diphenyl phosphate (0.1equiv.). After the addition of HPMC-solution (40-60 cps, 2 wt % inMillipore water, 1.25 mL) and the ketone (1.2 equiv.) the reactionmixture was vigorously stirred at room temperature until LCMS or TLCshowed full conversion of the starting materials. The mixture wasquenched with a saturated solution of sodium hydrogen carbonate in water(1 mL), diluted with EtOAc (3 mL) and stirred for 2 min. After theaddition of a saturated solution of sodium sulfate (2 mL) the phaseswere separated and the aqueous phase was further extracted with EtOAc(3×). The combined organic layers were dried over sodium sulfate. Thecrude product was purified by flash chromatography on silica gel.

18.2 Preparation of 4-methoxy-N-(1-phenylethyl)aniline

Following the general procedure using p-anisidine (62.0 mg, 0.50 mmol,1.0 equiv.), borane-2-picoline complex (64.6 mg, 0.60 mmol, 1.2 equiv.),diphenyl phosphate (12.6 mg, 0.05 mmol, 0.1 equiv.) and acetophenone(72.6 mg, 0.60 mmol, 1.2 equiv.) the reaction was stirred for 48 h atroom temperature. After column chromatography on silica gel (0-100%ethyl acetate-heptane) the product was obtained as a colorless oil (88mg, 0.39 mmol, 77%).

ESI-MS: m/z (%): 228.1 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.36-7.25 (m, 4H), 7.22-7.17 (m, 1H),6.70-6.64 (m, 2H), 6.47-6.42 (m, 2H), 4.38 (q, J=6.7 Hz, 1H), 3.72(s_(br), 1H), 3.65 (s, 3H), 1.46 (d, J=6.8 Hz, 3H).

19. Introduction of Protective Groups General Procedure forBoc-Protections of Primary Amines

A 5 mL microwave vial was charged with the amine (1.0 equiv.) and aHPMC-solution (40-60 cps, 2 wt % in Millipore water, 1.5 mL). After theaddition of di-tert-butyl dicarbonate (1.1 equiv.) and trimethylamine(1.1 equiv.) the reaction mixture was stirred at room temperature untilLCMS or TLC showed full conversion of the starting materials. Ethylacetate (1 mL) was added followed by a saturated solution of sodiumsulfate in water (2 mL). The mixture was filtered through a plug ofneutral aluminum oxide, which was washed with ethyl acetate. The organicphase was dried over sodium sulfate and the product was obtained afterremoval of the solvent or after column chromatography on silica gel.

19.1 Preparation of tert-butyl(1,2,3,4-tetrahydronaphthalen-2-yl)carbamate

Following the general procedure using1,2,3,4-tetrahydronaphthalen-2-amine (74.0 mg, 0.50 mmol, 1.0 equiv.),di-tert-butyl dicarbonate (121 mg, 0.55 mmol, 1.1 equiv.) andtrimethylamine (56.0 mg, 0.55 mmol, 1.1 equiv) the reaction was stirredfor 30 min at room temperature. The product was obtained as a whitesolid (80 mg, 0.32 mmol, 64%).

ESI-MS: m/z (%): 270.4 (100, [M+Na]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.14-7.02 (m, 4H), 4.70-4.60 (m, 1H),4.03-3.92 (m, 1H), 3.15-3.06 (m, 1H), 2.93-2.82 (m, 2H), 2.66-2.58 (m,1H), 2.10-2.02 (m, 1H), 1.78-1.69 (m, 1H), 1.45 (s, 9H).

General Procedure for Z-Protections of Primary Amines

A 5 mL microwave vial was charged with the amine (1.0 equiv.) and aHPMC-solution (40-60 cps, 2 wt % in Millipore water, 1.5 mL). After theaddition of dibenzyl dicarbonate (1.0 equiv.) the reaction mixture wasstirred at room temperature until LCMS or TLC showed full conversion ofthe starting materials. Ethyl acetate (1 mL) was added followed by asaturated solution of sodium sulfate in water (2 mL). The organic phasewas dried over sodium sulfate and the product was obtained after columnchromatography on silica gel.

19.2 Preparation of Benzyl (4-(cyanomethyl)phenyl)carbamate

Following the general procedure using 4-aminophenylacetonitrile (66.0mg, 0.50 mmol, 1.0 equiv) and dibenzyl dicarbonate (143.0 mg, 0.50 mmol,1.0 equiv) the reaction was stirred for 20 min at room temperature.After column chromatography on silica gel (0-1%dichloromethane-methanol) the product was obtained as a white solid (91mg, 0.34 mmol, 68%).

ESI-MS: m/z (%): 267.1 (80, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.51-6.84 (m, 10H), 5.18 (s, 2H), 3.66(s, 2H).

General Procedure for Acetyl Protections of Primary Amines

A 5 mL microwave vial was charged with the amine (1.0 equiv.) and aHPMC-solution (40-60 cps, 2 wt % in Millipore water, 1.5 mL). After theaddition of acetic anhydride (1.1 equiv.) and triethylamine (1.5 equiv.)the reaction mixture was stirred at room temperature until LCMS or TLCshowed full conversion of the starting materials. Ethyl acetate (1 mL)was added followed by a saturated solution of sodium sulfate in water (1mL). The mixture was filtered through a plug of silica, which was washedwith ethyl acetate. The organic phase was dried over sodium sulfate andthe product was obtained after removal of the solvent or after columnchromatography on silica gel.

19.3 Preparation of N-(1,2,3,4-tetrahydronaphthalen-2-yl)acetamide

Following the general procedure using1,2,3,4-tetrahydronaphthalen-2-amine (74.0 mg, 0.50 mmol, 1.0 equiv.),acetic anhydride (56.4 mg, 0.55 mmol, 1.1 equiv.) and trimethylamine(76.0 mg, 0.75 mmol, 1.5 equiv) the reaction was stirred for 10 min atroom temperature. Ethyl acetate (1 mL) was added followed by a saturatedsolution of sodium sulfate in water (1 mL). The crude reaction mixturewas filtered through a plug of silica. The organic phase was dried oversodium sulfate. After removal of the solvent the product was obtained asa white solid (61 mg, 0.32 mmol, 64%).

ESI-MS: m/z (%): 190.4 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.19-6.99 (m, 4H), 5.87 (s, 1H),4.33-4.21 (m, 1H), 3.16-3.05 (m, 1H), 2.96-2.80 (m, 2H), 2.68-2.60 (m,1H), 2.08-2.01 (m, 1H), 1.97 (s, 3H), 1.81-1.72 (m, 1H).

General Procedure for Acetyl Protections of Primary Amines in HighConcentrations

A 5 mL microwave vial was charged with the amine (1.0 equiv.) and aHPMC-solution (40-60 cps, 2 wt % in Millipore water, 0.165 mL). Afterthe addition of acetic anhydride (1.1 equiv.) and triethylamine (1.2equiv.) the reaction mixture was stirred for at room temperature untilLCMS or TLC showed full conversion of the starting materials.

19.4 Preparation ofN-(4-(5-cyano-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridin-3-yl)phenylacetamide

Following the general procedure using3-(4-aminophenyl)-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile(35 mg, 0.12 mmol, 1.0 equiv.), acetic anhydride (13.9 mg, 0.14 mmol,1.1 equiv.) and triethylamine (15.0 mg, 0.15 mmol, 1.2 equiv.) thereaction was stirred for 5 min at room temperature. After the additionof brine (0.3 mL) the formed solid was filtered off, washed with water(0.5 mL) and dried. The product was obtained as an off-white solid (40mg, 0.12 mmol, quant.).

ESI-MS: m/z (%): 326.1 (100, [M+H]⁺).

¹H NMR (600 MHz, dmso): δ [ppm]: 10.79 (s, 1H), 9.93 (s, 1H), 7.63-7.26(m, 4H), 6.57 (s, 1H), 2.05 (s, 3H).

19.5 Preparation ofN-(4-(6-cyano-7-hydroxy-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]-pyridin-1-yl)phenyl)acetamide

Following the general procedure using1-(4-aminophenyl)-7-hydroxy-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carbonitrilehydrochloride (32 mg, 0.11 mmol, 1.0 equiv.), acetic anhydride (11.9 mg,0.12 mmol, 1.1 equiv.) and triethylamine (34.2 mg, 0.34 mmol, 3.2equiv.) the reaction was stirred for 1 h at room temperature. After theaddition of brine (1.0 mL) the formed solid was filtered off, washedwith water (0.5 mL) and dried. The product was obtained as an off-whitesolid (20 mg, 0.07 mmol, 62%).

ESI-MS: m/z (%): 309.2 (100, [M+H]⁺).

¹H NMR (500 MHz, dmso): δ [ppm]: 9.98 (s, 1H), 9.69 (s, 1H), 7.66-7.18(m, 4H), 6.93 (d, J=2.9 Hz, 1H), 5.85 (d, J=3.0 Hz, 1H), 2.06 (s, 3H).

19.6 Preparation of ethyl 3-acetamido-1H-pyrrole-2-carboxylate(10154514-1934)

Following the general procedure using ethyl3-amino-H-pyrrole-2-carboxylate (100 mg, 0.64 mmol, 1.0 equiv.), aceticanhydride (71.4 mg, 0.70 mmol, 1.1 equiv.) and a HPMC-solution (40-60cps, 2 wt % in Millipore water, 0.212 mL) the reaction was stirred for10 min at room temperature. After the addition of ethyl acetate (20.0mL) and a saturated solution of sodium sulfate in water (0.2 mL) thephases were separated. The organic layer was dried over sodium sulfate.The product was obtained after removal of the solvent (126 mg, 0.61mmol, 95%).

ESI-MS: m/z (%): 197.1 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 9.17 (s, 1H), 8.55 (s, 1H), 7.07-7.04(m, 1H), 6.85-6.78 (m, 1H), 4.35 (q, J=7.1 Hz, 2H), 2.19 (s, 3H), 1.38(t, J=7.1 Hz, 3H).

20. One Pot Multi Step Reactions 20.1 One-Pot Two Step ReactionIncluding Double Nucleophilic Substitution with Ring Formation to anAzetidine and Subsequent Ester Hydrolysis General Procedure for aOne-Pot Azetidine Formation and Ester Hydrolysis

A 5 mL microwave vial was charged with the primary amine (1.0 equiv.),the bis-triflate (1.5 equiv.) and a HPMC-solution (40-60 cps, 2 wt % inMillipore water, 1.0 mL). After the addition of potassium hydroxide (6.0equiv.) the mixture was stirred at 50° C. for the indicated time. Theproduct was obtained reversed phase high pressure liquid chromatographyof the crude reaction mixture.

20.1.1 Preparation of3-methyl-1-(1,2,3,4-tetrahydronaphthalen-2-yl)azetidine-3-carboxylicAcid

Following the general procedure for a one-pot azetidine formation andester hydrolysis using 1,2,3,4-tetrahydronaphthalen-2-amine (73.6 mg,0.50 mmol, 1.0 equiv.), methyl2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2-((((trifluoromethyl)sulfonyl)oxy)-methyl)propanoate(309 mg, 0.75 mmol, 1.5 equiv.) and potassium hydroxide (168 mg, 3.00mmol, 6.0 equiv.) the reaction was stirred for 2 h at 50° C. Afterreversed phase high pressure liquid chromatography the product wasobtained as a white solid (91 mg, 0.37 mmol, 74%).

ESI-MS: m/z (%): 246.4 (100, [M+H]⁺).

¹H NMR (600 MHz, DMSO-d₆): δ [ppm]: 7.21-7.06 (m, 4H), 4.48-4.38 (m,2H), 4.14-4.05 (m, 2H), 3.71 (s_(br), 1H), 3.67-3.57 (m, 1H), 3.17-3.09(m, 1H), 2.92-2.47 (m, 4H), 2.17-2.05 (m, 1H), 1.54 (s, 3H).

¹³C NMR (126 MHz, DMSO-d₆) δ [ppm]: 174.78, 135.25, 132.57, 129.52,128.98, 126.82, 126.52, 60.87, 59.63, 59.61, 38.74, 29.65, 27.23, 23.46,21.80.

20.2 One-Pot Four Step Reaction Including Boc-Protection of an AminoGroup, Nucleophilic Substitution, Deprotection and Michael Addition ofan N Nucleophile 20.2.2 Preparation of ethyl3-(((S)-7-((2-ethyl-6-fluorobenzyl)oxy)chroman-3-yl)amino)-2-(hydroxymethyl)propanoate

(S)-3-Aminochroman-7-ol hydrochloride (500 mg, 2.48 mmol, 1.0 eq.) anddi-tert-butyl dicarbonate (635 μl, 2.76 mmol, 1.1 eq.) were loaded intoa 5.0 mL microwave vial opened in the air and containing a magnetic stirbar and Teflon-lined septum. HPMC in water solution (Matrocel E5, 8.3 mlof 2 wt % in degassed Millipore water) was added followed bytrimethylamine (382 μl, 2.73 mmol, 1.1 eq.). The microwave tube wasclose with a septa and the reaction mixture was stirred at roomtemperature for 5 minutes. Completion of the reaction was confirmed byLC/MS.

To the reaction mixture was added2-(bromomethyl)-1-ethyl-3-fluorobenzene (592 mg, 2.73 mmol, 1.1 eq.) andsodium hydroxide (129 mg, 3.22 mmol, 1.3 eq.) and the suspension wasstirred at 65° C. for 15 min. As the reaction did not go to completionan extra 1.0 eq. of sodium hydroxide and 0.2 eq. of2-(bromomethyl)-1-ethyl-3-fluorobenzene were added and the reactionmixture was stirred at 65° C. for an extra 15 min. Completion of thereaction was confirmed by LC/MS.

12N HCl was added dropwise to adjust the pH of the mixture to 4.p-Toluenesulfonic acid (1.71 g, 9.92 mmol, 4.00 eq.) was added to themixture in two portions. The mixture was then vigorously stirred andheated at 65° C. for 15 min. As no reaction was observed after 15 minextra p-toluenesulfonic acid (850 mg, 4.96 mmol, 2.00 eq.) was added andthe reaction was complete after 1 h.

The mixture was cooled to room temperature and trimethylamine (1.74 mL,12.40 mmol, 5.00 eq.) was added in order to adjust the pH to 9. Ethyl2-(hydroxymethyl)acrylate (323 mg, 2.48 mmol, 1.00 eq.) was then addedand the mixture was stirred at room temperature for 12 h. LCMS showssome starting material left. An extra 0.50 eq. of ethyl2-(hydroxymethyl)acrylate (162 mg, 1.24 mmol) was added and the mixturewas stirred for an extra 3 h.

To the reaction mixture were added ethyl acetate and saturated aqueoussodium sulfate solution. The mixture was stirred at room temperature for10 min and filtered through celite to remove the solid. The solid waswashed three times with ethyl acetate. The organic phase was separatedfrom the aqueous layer. The combined ethyl acetate phases were dried invacuo to give 1.00 g of crude material. After column chromatography onsilica gel (0-5% dichloromethane-methanol in presence of 1%triethylamine) the product was obtained as a colorless oil (810 mg, 1.88mmol, 76%).

ESI-MS: m/z (%): 432.0 (100, [M+H]⁺)

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.33-7.29 (m, 1H), 7.08 (d, J=7.6 Hz,1H), 7.00-6.92 (m, 2H), 6.59 (d, J=8.3 Hz, 1H), 6.54 (s, 1H), 5.07 (s,2H), 4.25-4.09 (m, 3H), 4.08-3.90 (m, 3H), 3.33-3.21 (m, 1H), 3.23-3.07(m, 2H), 3.07-2.95 (m, 1H), 2.86-2.70 (m, 3H), 2.64 (dd, J=15.9, 6.6 Hz,2H), 1.34-1.18 (m, 6H).

21. Cyclopropanation General Procedure for Cyclopropanations withIn-Situ Formation of the Diazo Compound from Glycine Ethyl EsterHydrochloride

A 10 mL vial was charged with the alkene (1.0 equiv.),meso-tetraphenylporphyrin iron(III) chloride complex (0.01 equiv.) andglycine ethyl ester hydrochloride (2.0 equiv.). After the addition ofdichloroethane (0.4 mL per mmol of alkene), a HPMC-solution (40-60 cps,2 wt % in Millipore water, 4 mL per mmol of alkene) and acetic acid(0.15 equiv.), the mixture was heated to 40° C. Sodium nitrite (2.4equiv) was added and the mixture was stirred for 20 h at 40° C. Themixture was diluted with ethyl acetate (2 mL/mmol) and a saturatedsolution of sodium sulfate (2 mL/mmol). After extraction with ethylacetate (3×) the combined organic layers were dried over sodium sulfate.The crude product was purified by flash chromatography on silica gel.

21.1 Preparation of ethyl2-([1,1′-biphenyl]-4-yl)cyclopropanecarboxylate

Following the general procedure using 4-vinylbiphenyl (90 mg, 0.5 mmol,1.0 equiv.), meso-tetraphenylporphyrin iron(III) chloride complex (3.5mg, 0.005 mmol, 0.01 equiv.), glycine ethyl ester hydrochloride (140 mg,1.0 mmol, 2.0 equiv.), acetic acid (4.5 mg, 0.075 mmol, 0.15 mmol) andsodium nitrite (83 mg, 1.2 mmol, 2.4 equiv.) the reaction mixture wasstirred for 20 h at 40° C. After column chromatography on silica gel(0-100% ethyl acetate-heptane) the product was obtained as a pale yellowsolid (50 mg, 0.19 mmol, 38%). The product was a mixture oftrans:cis=8:1.

Analytical data for the trans product:

ESI-MS: m/z (%): 267.2 (100, [M+H]⁺).

¹H NMR (600 MHz, CDCl₃): δ [ppm]: 7.62-7.09 (m, 9H), 4.17 (q, J=7.1 Hz,2H), 2.60-2.51 (m, 1H), 1.98-1.90 (m, 1H), 1.70-1.58 (m, 1H), 1.38-1.31(m, 1H), 1.28 (t, J=7.1 Hz, 3H).

We claim:
 1. A method of carrying out an organic reaction in a solventcontaining at least 90% by weight, based on the total weight of thesolvent, of water, which method comprises reacting the reagents in saidsolvent in the presence of a cellulose derivative as a surfactant whichis selected from the group consisting of cellulose modified with one ormore alkylene oxides or other hydroxyalkyl precursors, andalkylcellulose; where the organic reaction is not a polymerization oroligomerization reaction of olefinically unsaturated compounds; andwhere the organic reaction is a transition metal catalyzed reaction inwhich a transition metal catalyst is used; where the transition metalcatalyzed reaction is a transition metal catalyzed C—C couplingreaction; a transition metal catalyzed reaction involving C—N bondformation which is an Au-catalyzed cyclodehydratization of α,β-aminoalcohols containing a C—C triple bond; a transition metal catalyzedreaction involving C—O bond formation; a transition metal catalyzedreaction involving C—S bond formation; a transition metal catalyzedreaction involving C—B bond formation; or a transition metal catalyzedreaction involving C-halogen bond formation; or a C—C coupling reactionnot requiring transition metal catalysis which is selected from thegroup consisting of reactions of carbonyl or nitrile compounds andpericyclic reactions; a nucleophilic substitution reaction; a reductionor an oxidation reaction; or an ester formation reaction or an esterhydrolysis reaction.
 2. The method as claimed in claim 1, where thecellulose derivative has a viscosity of from 1 to 150000 mPa·s,determined as a 2% by weight aqueous solution, relative to the weight ofwater.
 3. The method as claimed in claim 1, where in the cellulosederivative 5 to 70% of the hydrogen atoms in the hydroxyl groups of thecellulose on which the cellulose derivative is based are replaced by ahydroxyalkyl and/or alkyl group.
 4. The method as claimed in claim 1,where the cellulose modified with one or more alkylene oxides or otherhydroxyalkyl precursors is selected from the group consisting ofhydroxyalkylcelluloses which are celluloses in which a part of thehydrogen atoms of the OH groups is replaced by a C₂-C₄-hydroxyalkylgroup; hydroxyalkylalkylcelluloses which are celluloses in which a partof the hydrogen atoms of the OH groups is replaced by aC₂-C₄-hydroxyalkyl group and a part of the hydrogen atoms of the OHgroups is replaced by a C₁-C₃-alkyl group; and alkylcelluloses which arecelluloses in which a part of the hydrogen atoms of the OH groups isreplaced by a C₁-C₃-alkyl group.
 5. The method as claimed in any claim4, where the cellulose derivative is selected from the group consistingof hydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxyethylmethylcellulose, ethylhydroxyethylcellulose,hydroxyethylcellulose, methylcellulose and ethylcellulose.
 6. The methodas claimed in claim 5, where the cellulose derivative ishydroxypropylmethylcellulose.
 7. The method as claimed in claim 1, wherethe cellulose derivative is used in an amount of from 0.01 to 15% byweight, based on the weight of the solvent, or, alternatively, based onthe weight of water.
 8. The method as claimed in claim 1, where theweight ratio of the cellulose derivative and all reagents is from 1:1 to1:200.
 9. The method as claimed in claim 1, where at least one of thereagents has a water solubility of at most 100 g per 1 l of water at 20°C.+/−20% and 101325 Pascal+/−20%.
 10. The method as claimed in claim 1,where the organic reaction is a transition metal catalyzed reaction inwhich a transition metal catalyst is used.
 11. The method as claimed inclaim 10, where the transition metal catalyst is not a catalystsupported on the cellulose derivative.
 12. The method as claimed inclaim 10, where the transition metal is selected from the groupconsisting of Fe, Ru, Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, Au, and Zn. 13.The method as claimed in claim 1, where the transition metal catalyzedC—C-coupling reaction is selected from the group consisting of theSuzuki-Miyaura reaction, Negishi coupling, Heck reaction, C—C couplingreactions involving C—H activation different from Heck reaction,Sonogashira coupling, Stille coupling, Grubbs olefin metathesis, 1,4additions of organoborane compounds to α,β-olefinically unsaturatedcarbonyl compounds, Kumada coupling, Hiyama coupling, Ullmann reactions,Glaser coupling inclusive the Eglinton and the Hay coupling,Cadiot-Chodkiewicz coupling, the Fukuyama coupling, hydroformylation andcyclopropanation.
 14. The method as claimed in claim 13, where thetransition metal catalyzed C—C-coupling reaction is a Suzuki-Miyaurareaction in which an organoboron compound is reacted with an organichalogenide or sulfonate in the presence of a transition metal catalystand optionally a base; where the organoboron compound is a compound offormula R¹—BY₂, where R¹ is an alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl orheteroaryl group and Y is an alkyl, O-alkyl or hydroxyl group, or thetwo substituents Y form together with the boron atom they are bound to amono-, bi- or polycyclic ring; or the organoboron compound is a compoundof formula R¹—BF₃M, where M is a metal equivalent; and the organichalogenide or sulfonate is a compound of formula R²—(Z)_(n), where R² isan alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl group, Zis a halogenide or sulfonate group, and n is 1, 2, 3 or 4; where thealkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl groupsR¹ and R² can carry one or more substituents.
 15. The method as claimedin claim 13, where the transition metal catalyzed C—C-coupling reactionis a Sonogashira reaction, where an aryl, heteroaryl or vinyl halogenideor sulfonate is reacted with a terminal alkyne in the presence of atransition metal catalyst, optionally of a copper(I) salt, andoptionally of a base; where the aryl, heteroaryl or vinyl halogenide orsulfonate is a compound of formula R²—(Z)_(n), where R² is a terminalalkenyl, aryl or heteroaryl group, Z is a halogenide or sulfonate groupand n is 1, 2, 3 or 4; the terminal alkyne is a compound of formulaH—C≡C—R¹, where R¹ is hydrogen or an alkyl, alkenyl, alkapolyenyl,alkynyl (provided that the alkyne group is not terminal), alkapolyynyl(provided there is no terminal alkyne group in this radical), mixedalkenyl/alkynyl (provided there is no terminal alkyne group in thisradical), cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl,heteroaryl or silyl group Si(R¹⁴′)₃, where the alkyl, alkenyl,alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, aryl, heterocyclyl and heteroaryl groups R¹ and R² cancarry one or more substituents; and where each R¹⁴′ is independentlyselected from the group consisting of hydrogen, halogen, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, and phenyl, optionally substituted with 1, 2, 3,4, or 5 radicals selected from the group consisting of halogen, cyano,nitro, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy and C₁-C₆-haloalkoxy.16. The method as claimed in claim 13, where the transition metalcatalyzed C—C coupling reaction is a Heck reaction, where an aryl,heteroaryl, benzyl, vinyl or alkyl halogenide or sulfonate (the alkylgroup must not contain any β-hydrogen atoms) is reacted with anolefinically unsaturated compound in the presence of a transition metalcatalyst and optionally in the presence of a base; where the aryl,heteroaryl, benzyl, vinyl or alkyl halogenide or sulfonate is a compoundof the formula R²—(Z)_(n), where R² is an aryl, heteroaryl, benzyl,vinyl or alkyl group, where the alkyl group must not contain anyβ-hydrogen atoms, Z is a halogen atom or a sulfonate group, and n is 1,2, 3 or 4, and the olefinically unsaturated compound is a compound ofthe formula R¹(H)C═C(R³)(R⁴) where R¹, R³, and R⁴, independently of eachother, are selected from the group consisting of hydrogen, alkyl,alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl,halogen, cyano, nitro, azido, —SCN, —SF₅, OR¹¹, S(O)_(m)R¹¹,NR^(12a)R^(12b), C(═O)R¹³, C(═S)R¹³, C(═NR^(12a))R¹³, —Si(R¹⁴)₃,cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, where the five last-mentioned substituents may carryone or more substituents R¹⁵; aryl which may be substituted by one ormore radicals R¹⁵; heterocyclyl which may be substituted by one or moreradicals R¹⁵; and heteroaryl which may be substituted by one or moreradicals R¹⁵; where each R¹¹ is independently selected from the groupconsisting of hydrogen, cyano, alkyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, alkenyl,alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, where thealiphatic and cycloaliphatic moieties in the 11 last-mentioned radicalsmay be partially or fully halogenated and/or may be substituted by oneor more radicals R¹⁷, -alkyl-C(═O)OR¹⁸, -alkyl-C(═O)N(R^(12a))R^(12b),-alkyl-C(═S)N(R^(12a))R^(12b), -alkyl-C(═NR¹²)N(R^(12a))R^(12b),—Si(R¹⁴)₃, —S(O)_(m)R¹⁸, —S(O)_(m)N(R^(12a))R^(12b), —N(R^(12a))R^(12b),—N═C(R¹⁶)₂, —C(═O)R¹³, —C(═O)N(R^(12a))R^(12b), —C(═S)N(R^(12a))R^(12b),—C(═O)OR¹⁸, aryl, optionally substituted with one or more substituentsR¹⁵; heterocyclyl, optionally substituted with one or more substituentsR¹⁵; and heteroaryl, optionally substituted with one or moresubstituents R¹⁵; and R¹¹ in the group —S(O)_(m)R¹¹ is additionallyselected from the group consisting of alkoxy and haloalkoxy; R¹²,R^(12a) and R^(12b), independently of each other and independently ofeach occurrence, are selected from the group consisting of hydrogen,cyano, alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, alkenyl, alkapolyenyl,alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, wherein the 11last-mentioned aliphatic and cycloaliphatic radicals may be partially orfully halogenated and/or may be substituted by one or more substituentsR¹⁹, —OR²⁰, —NR^(21a)R^(21b), —S(O)_(m)R²⁰, —C(═O)N(R^(21a)R^(21b)),—C(═O)NR²¹N(R^(21a)R^(21b)), —Si(R¹⁴)₃, —C(═O)R¹³, aryl which may besubstituted with 1, 2, 3, 4, or 5 substituents R¹⁵, heterocyclyl whichmay be substituted with one or more substituents R¹⁵; and heteroarylwhich may be substituted with one or more substituents R¹⁵; or R^(12a)and R^(12b), together with the nitrogen atom to which they are bound,form a saturated, partially unsaturated or maximally unsaturatedheterocyclic or heteroaromatic ring, where the ring may further contain1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected fromthe group consisting of O, S, N, SO, SO₂, C═O and C═S as ring members,wherein the heterocyclic or heteroaromatic ring may be substituted with1, 2, 3, 4 or 5 independent R¹⁵ substituents; or R^(12a) and R^(12b)together form a group ═C(R²²)₂, ═S(O)_(m)(R²⁰)₂, ═NR^(21a) or ═NOR²⁰;each R¹³ is independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, where the aliphatic andcycloaliphatic moieties in the 11 last-mentioned radicals may bepartially or fully halogenated and/or may be substituted by one or moreradicals R¹⁷; aryl, optionally substituted with one or more radicalsR¹⁵; heterocyclyl, optionally substituted with one or more radicals R¹⁵;heteroaryl, optionally substituted with one or more radicals R¹⁵; OR²⁰,—S(O)_(m)R²⁰, —N(R^(21a))R^(21b), —C(═O)N(R^(21a))R^(21b),—C(═S)N(R^(21a))R^(21b) and —C(═O)OR²⁰; each R¹⁴ is independentlyselected from the group consisting of hydrogen, halogen, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, and phenyl, optionally substituted with 1, 2, 3,4, or 5 radicals R¹⁵; each R¹⁵ is independently selected from the groupconsisting of halogen, azido, nitro, cyano, —OH, —SH, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, —Si(R²³)₃; C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl,C₂-C₂₀-alkapolyenyl, C₂-C₂₀-alkynyl, C₂-C₂₀-alkapolyynyl, mixedC₂-C₂₀-alkenyl/alkynyl, wherein the six last-mentioned aliphaticradicals may be partially or fully halogenated and/or may carry one ormore radicals selected from the group consisting of OH, C₁-C₂₀-alkoxy,C₁-C₂₀-haloalkoxy, SH, C₁-C₂₀-alkylthio, C₁-C₂₀-haloalkylthio,C₁-C₂₀-alkylsulfinyl, C₁-C₂₀-haloalkylsulfinyl, C₁-C₂₀-alkylsulfonyl,C₁-C₂₀-haloalkylsulfonyl, —Si(R²³)₃, oxo, C₃-C₈-cycloalkyl,C₃-C₈-cycloalkenyl, C₈-C₂₀-cycloalkynyl, mixedC₃-C₂₀-cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl, heterocyclyland heteroaryl, wherein the 8 last-mentioned cyclic radicals may in turnbe partially or fully halogenated and/or may carry one or more radicalsselected from the group consisting of OH, C₁-C₂₀-alkoxy,C₁-C₂₀-haloalkoxy, SH, C₁-C₂₀-alkylthio, C₁-C₂₀-haloalkylthio,C₁-C₂₀-alkylsulfinyl, C₁-C₂₀-haloalkylsulfinyl, C₁-C₂₀-alkylsulfonyl,C₁-C₂₀-haloalkylsulfonyl, —Si(R²³)₃, oxo, C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₂-C₆-alkenyl, C₂-C₆-haloalkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkynyl,C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, C₈-C₂₀-cycloalkynyl, mixedC₃-C₂₀-cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl, heterocyclyland heteroaryl, wherein the 8 last mentioned radicals may in turn beunsubstituted, partially or fully halogenated and/or carry 1, 2 or 3substituents selected from the group consisting of cyano, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkoxycarbonyland C₁-C₆-haloalkoxycarbonyl; C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl,C₈-C₂₀-cycloalkynyl, mixed C₃-C₂₀-cycloalkenyl/cycloalkynyl,polycarbocyclyl, wherein the 5 last-mentioned cycloaliphatic radicalsmay be partially or fully halogenated and/or may carry one or moreradicals selected from the group consisting of cyano, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and oxo; aryl, O-aryl,heterocyclyl, O-heterocyclyl, heteroaryl and O-heteroaryl, wherein thecyclic moieties in the 6 last mentioned radicals may be unsubstituted,partially or fully halogenated and/or carry 1, 2 or 3 substituentsselected from the group consisting of C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkoxycarbonyl andC₁-C₆-haloalkoxycarbonyl; or two R¹⁵ present together on the same atomof an unsaturated or partially unsaturated ring may be ═O, ═S,═N(C₁-C₆-alkyl), ═NO(C₁-C₆-alkyl), ═CH(C₁-C₄-alkyl) or═C(C₁-C₄-alkyl)C₁-C₄-alkyl; or two R¹⁵ on two adjacent carbon ornitrogen atoms form together with the carbon or nitrogen atoms they arebonded to a 4-, 5-, 6-, 7- or 8-membered saturated, partiallyunsaturated or maximally unsaturated, including heteroaromatic, ring,wherein the ring may contain 1, 2, 3 or 4 heteroatoms or heteroatomgroups selected from the group consisting of N, O, S, NO, SO and SO₂, asring members, and wherein the ring optionally carries one or moresubstituents selected from the group consisting of halogen, cyano,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy; eachR¹⁶ is independently selected from the group consisting of hydrogen,halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,C₂-C₆-alkynyl and C₂-C₆-haloalkynyl, wherein the six last-mentionedaliphatic radicals may carry 1 or 2 radicals selected from the groupconsisting of CN, C₃-C₄-cycloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy andoxo; each R¹⁷ is independently selected from the group consisting ofcyano, nitro, —OH, —SH, —SCN, —SF₅, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl,C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl,—Si(R¹⁴)₃, C₃-C₈-cycloalkyl which may be unsubstituted, partially orfully halogenated and/or may carry 1 or 2 radicals selected from thegroup consisting of C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and oxo; aryl,aryloxy, heterocyclyl, heterocyclyloxy, heteroaryl and heteroaryloxy,where the cyclic moiety in the 6 last-mentioned radicals may beunsubstituted, partially or fully halogenated and/or carry 1, 2, 3, 4 or5 substituents R¹⁵; or two R¹⁷ present on the same carbon atom (of analkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, alkenyl, alkapolyenyl,alkynyl, alkapolyynyl or mixed alkenyl/alkynyl group) may together be═O, ═CH(C₁-C₄-alkyl), ═C(C₁-C₄-alkyl)C₁-C₄-alkyl, ═N(C₁-C₆-alkyl) or═NO(C₁-C₆-alkyl); and R¹⁷ as a substituent on a cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl orpolycarbocyclyl ring is additionally selected from the group consistingof C₁-C₆-alkyl, C₂-C₆-alkenyl and C₂-C₆-alkynyl, wherein the threelast-mentioned aliphatic radicals may be unsubstituted, partially orfully halogenated and/or may carry 1 or 2 substituents selected from thegroup consisting of CN, C₃-C₄-cycloalkyl, C₃-C₄-halocycloalkyl,C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and oxo; each R¹⁸ is independentlyselected from the group consisting of hydrogen, cyano, —Si(R¹⁴)₃,C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, C₂-C₂₀-alkynyl, wherein the threelast-mentioned aliphatic radicals may be unsubstituted, partially orfully halogenated and/or may carry 1 or 2 radicals selected from thegroup consisting of C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl,C₁-C₂₀-alkoxy, C₁-C₂₀-haloalkoxy, C₁-C₂₀-alkylthio,C₁-C₂₀-haloalkylthio, C₁-C₂₀-alkylsulfinyl, C₁-C₂₀-haloalkylsulfinyl,C₁-C₂₀-alkylsulfonyl, C₁-C₂₀-haloalkylsulfonyl and oxo; C₃-C₈-cycloalkylwhich may be unsubstituted, partially or fully halogenated and/or maycarry 1 or 2 radicals selected from the group consisting of C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₃-C₄-cycloalkyl, C₃-C₄-halocycloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy, C₁-C₄-alkylthio, C₁-C₄-haloalkylthio,C₁-C₄-alkylsulfinyl, C₁-C₄-haloalkylsulfinyl, C₁-C₄-alkylsulfonyl,C₁-C₄-haloalkylsulfonyl and oxo; aryl, heterocyclyl and heteroaryl,wherein the 3 last-mentioned radicals may be unsubstituted, partially orfully halogenated and/or carry 1, 2 or 3 substituents selected from thegroup consisting of C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkoxycarbonyl and C₁-C₆-haloalkoxycarbonyl; andR¹⁸ in the group S(O)_(m)R¹⁸ is additionally selected from the groupconsisting of C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, aryloxy, heterocyclyloxyand heteroaryloxy; each R¹⁹ is independently selected from the groupconsisting of halogen, nitro, cyano, —OH, —SH, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, Si(R¹⁴)₃; C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, wherein the two last-mentioned cycloaliphaticradicals may carry one or more radicals selected from the groupconsisting of cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and oxo; aryl,aryloxy, heterocyclyl, heterocyclyloxy, heteroaryl and heteroaryloxy,wherein the 6 last mentioned radicals may be unsubstituted, partially orfully halogenated and/or carry 1, 2 or 3 substituents selected from thegroup consisting of C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkoxycarbonyl and C₁-C₆-haloalkoxycarbonyl;each R²⁰ is independently defined as R¹⁸; R²¹, R^(21a) and R^(21b),independently of each other and independently of each occurrence, areselected from the group consisting of hydrogen, cyano, alkyl,cycloalkyl, alkenyl, alkynyl, wherein the four last-mentioned aliphaticand cycloaliphatic radicals may be partially or fully halogenated, aryl,aryl-C₁-C₄-alkyl, heterocyclyl, and heteroaryl, where the rings in the 4last mentioned radicals may be substituted with 1, 2, 3, 4, or 5substituents R¹⁵; or R^(21a) and R^(21b), together with the nitrogenatom to which they are bound, form a 3-, 4-, 5-, 6-, 7- or 8-memberedsaturated, partially unsaturated or maximally unsaturated heterocyclic,inclusive heteroaromatic, ring, where the ring may further contain 1, 2,3 or 4 heteroatoms or heteroatom-containing groups selected from thegroup consisting of O, S, N, SO, SO₂, C═O and C═S as ring members,wherein the heterocyclic ring may be substituted with 1, 2, 3, 4 or 5independent R¹⁵ substituents; each R²² is independently defined as R¹⁶;each R²³ is independently selected from the group consisting ofhydrogen, halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-haloalkoxy-C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl, and phenyl, optionally substituted with 1, 2, 3,4, or 5 radicals selected from the group consisting of halogen, cyano,nitro, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy and C₁-C₆-haloalkoxy;and m is 0, 1 or 2; where the alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolyynyl and mixed alkenyl/alkynyl groups R¹, R³ and R⁴, and thearyl, heteroaryl, benzyl, vinyl and alkyl groups R² can carry one ormore substituents.
 17. The method as claimed in claim 13, where thetransition metal catalyzed C—C-coupling reaction is a C—C couplingreaction involving C—H activation in which an aromatic or heteroaromatichalogenide or sulfonate is coupled with an aromatic or heteroaromaticcompound in the presence of a transition metal catalyst and in case thatan aromatic or heteroaromatic chloride, bromide or iodide is used,optionally also in the presence of a water-soluble silver(I) salt; wherethe aromatic or heteroaromatic halogenide or sulfonate is a compound offormula R²—Z, where R² is an aryl or heteroaryl group, Z is a halogenatom or a sulfonate group, and the aromatic or heteroaromatic is acompound of formula R¹—H, where R¹ is an aryl or heteroaryl group, wherethe aryl and heteroaryl groups R¹ and R² can carry one or moresubstituents.
 18. The method as claimed in claim 13, where thetransition metal catalyzed C—C-coupling reaction is a Stille reaction,where an organotin compound (organostannane) is reacted with an alkenyl,aryl, heteroaryl or acyl halide, sulfonate or phosphate in the presenceof a transition metal catalyst and optionally also in the presence of abase, where the organostannane compound is a compound of the formulaR¹—Sn(R^(a))₃, where R¹ is a an alkenyl, aryl or heteroaryl group andR^(a) is an alkyl group, and the alkenyl, aryl, heteroaryl or acylhalide, sulfonate or phosphate is a compound of the formula R²—(Z)_(n),where R² is an alkenyl, aryl, heteroaryl or acyl group, Z is a halogenatom, a sulfonate group or a phosphate group, and n is 1, 2, 3 or 4,where the alkenyl, aryl and heteroaryl groups R¹ and R² can carry one ormore substituents.
 19. The method as claimed in claim 13, where thetransition metal catalyzed C—C-coupling reaction is a Negishi reaction.20. The method as claimed in claim 13, where the transition metalcatalyzed C—C-coupling reaction is a Grubbs olefin metathesis, where twoolefinic compounds R¹R²C═CR³R⁴ and R⁵R⁶C═CR⁷R⁸ are reacted with eachother in the presence of a Grubbs catalyst, where R¹, R², R³, R⁴, R⁵,R⁶, R⁷ and R⁸, independently of each other, are selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, heterocyclyl, aryl, hetaryl, halogen, cyano, nitro,azido, —SCN, —SF₅, OR¹¹, S(O)_(m)R¹¹, NR^(12a)R^(12b), C(═O)R¹³,C(═S)R¹³, C(═NR^(12a))R¹³ and —Si(R¹⁴)₃; where R¹¹, R^(12a), R^(12b),R¹³ and R¹⁴ are independently as defined in claim 17; where the alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl andheteroaryl groups R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ can carry one ormore substituents.
 21. The method as claimed in claim 13, where thetransition metal catalyzed C—C coupling reaction is a 1,4-addition of anorganoborane compound to an α,β-olefinically unsaturated carbonylcompound in the presence of a transition metal catalyst, where theorganoboron compound is a compound of formula R¹—BY₂, where R¹ is analkyl, alkenyl, alkynyl, aryl or heteroaryl group and Y is an alkyl,O-alkyl or hydroxyl group, or the two substituents Y form together withthe boron atom they are bound to a mono-, bi- or polycyclic ring; or theorganoboron compound is a compound of formula R¹—BF₃M, where M is ametal equivalent, and the α,β-olefinically unsaturated carbonyl compoundis a compound of formula R²R³C═CR⁴—C(═O)—R⁵, where R², R³ and R⁴,independently of each other, are hydrogen, alkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl and R⁵ is hydrogen, alkyl, cycloalkyl,aryl, heteroaryl, OH, SH, alkoxy, alkylthio, NH₂, alkylamino ordialkylamino, where the alkyl (also as part of alkoxy, alkylthio,alkylamino or dialkylamino), alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl or heteroaryl groups R¹, R², R³, R⁴ and R⁵ can carry one or moresubstituents.
 22. The method as claimed in claim 13, where thetransition metal catalyzed C—C-coupling reaction is a cyclopropanation,where an olefinically unsaturated compound is reacted with a diazocompound in the presence of a transition metal catalyst, where theolefinically unsaturated compound is a compound of formula R¹R²C═CR³R⁴and the diazo compound is a compound of formula N₂═CR⁵R⁶, where R¹, R²,R³, R⁴, R⁵ and R⁶, independently of each other, are selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, heterocyclyl, aryl, hetaryl, halogen, cyano, nitro,azido, —SCN, —SF₅, OR¹¹, S(O)_(m)R¹¹, NR^(12a)R^(12b), C(═O)R¹³,C(═S)R¹³, C(═NR^(12a))R¹³ and —Si(R¹⁴)₃; where R¹¹, R^(12a), R^(12b),R¹³ and R¹⁴ are independently as defined in claim 17; where the alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl andheteroaryl groups R¹, R², R³, R⁴, R⁵ and R⁶ can carry one or moresubstituents.
 23. The method as claimed in claim 1, where the transitionmetal catalyzed reaction is a transition metal catalyzed reactioninvolving C—O bond formation, where the transition metal catalyzedreaction involving C—O bond formation is an Au-catalyzedcyclodehydratization of alkyne diols, an Au-catalyzed cyclization ofalkynenols, an Au-catalyzed cyclization of alkynones, an Au-catalyzedcyclization of allenones, or is the formation of alcohols or ethers viaC—O coupling.
 24. The method as claimed in claim 23, where thetransition metal catalyzed reaction involving C—O bond formation is anAu-catalyzed cyclodehydratization of an alkyne (I) carrying in α- andβ-position to the alkyne group two OH groups to the corresponding furane(II):

where R¹, R² and R³ are independently of each other H, alkyl,cycloalkyl, aryl, heterocyclyl or heteroaryl, where the alkyl,cycloalkyl, aryl, heterocyclyl or heteroaryl groups R¹, R² and R³ cancarry one or more substituents.
 25. The method as claimed in claim 23,where the transition metal catalyzed reaction involving C—O bondformation is the formation of alcohols or ethers via C—O coupling, wherean aromatic or heteroaromatic compound R¹—X, where R¹ is an aryl orheteroaryl group and X is a halogen atom or a pseudohalide group, isreacted with a metal hydroxide to yield an alcohol R¹—OH; or is reactedwith a hydroxyl compound R²—OH, where R² is alkyl, alkenyl,alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, heterocyclyl, aryl or heteroaryl, to yield an etherR¹—O—R², where the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl,mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl orheteroaryl groups R¹ and R² can carry one or more substituents.
 26. Themethod as claimed in claim 1, where the transition metal catalyzedreaction is a transition metal catalyzed reaction involving C—B bondformation, where the transition metal catalyzed reaction involving C—Bbond formation is a Miyaura borylation, where a halogenide or sulfonateR²—(Z)_(n), where R² is an alkenyl, aryl or heteroaryl group, Z is ahalogenide or sulfonate group and n is 1, 2, 3 or 4, is reacted with atetraalkoxydiboron (R¹O)₂B—B(OR¹)₂, where R¹ is alkyl or two R¹ bound onoxygen atoms bound in turn to the same B atom form together—C(CH₃)₃—C(CH₃)₂— (so that B(OR¹)₂ is the pinacolon ester of boronicacid), in the presence of a transition metal catalyst, and optionallyalso of a base, where the alkyl, alkenyl, aryl or heteroaryl groups R¹and R² can carry one or more substituents.
 27. The method as claimed inclaim 1, where the transition metal catalyzed reaction is a transitionmetal catalyzed reaction involving C-halogen bond formation, in which anaromatic or heteroaromatic compound R¹—H, where R¹ is aryl orheteroaryl, is reacted with a halogenating agent in the presence of atransition metal catalyst, to yield a compound R¹—X, where X is ahalogen atom, where the aryl or heteroaryl group R¹ can carry one ormore substituents.
 28. The method as claimed in claim 1, where theorganic reaction is a C—C coupling reaction not requiring transitionmetal catalysis, and is selected from the group consisting of reactionsof carbonyl or nitrile compounds and pericyclic reactions.
 29. Themethod as claimed in claim 28, where the C—C coupling reaction notrequiring transition metal catalysis is a Wittig reaction in which aphosphorous ylene or ylide (I) is reacted with a carbonyl compound (II)to an olefinically unsaturated compound (III) and a phosphorus oxide(IV)

where R¹ is an aryl group; R² and R³, independently of each other, arehydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl,heteroaryl, CN, C(O)R¹³, C(S)R¹³ or S(O)₂R¹¹, where R¹¹ and R¹³ are asdefined in claim 17; and R⁴ and R⁵ are independently of each otherhydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl orheteroaryl; where the alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl,heterocyclyl, aryl and heteroaryl groups R¹, R², R³, R⁴ and R⁵ can carryone or more substituents.
 30. The method as claimed in claim 28, wherethe C—C coupling reaction not requiring transition metal catalysis is aDiels-Alder reaction in which a conjugated diene is reacted with adienophile to a cyclohexene derivative.
 31. The method as claimed inclaim 28, where the C—C coupling reaction not requiring transition metalcatalysis is a Baylis-Hillman reaction in which an α,β-olefinicallyunsaturated carbonyl compound (I) is reacted with an aldehyde or anactivated ketone or derivative thereof (II) in the presence of anucleophilic catalyst and optionally in the presence of a metal-derivedLewis acid to a compound (III):

or in which α,β-olefinically unsaturated nitrile (IV) compound isreacted with a an aldehyde or an activated ketone or derivative thereof(II) in the presence of a nucleophilic catalyst and optionally in thepresence of a metal-derived Lewis acid to a compound (V):

where R¹, R² and R³ are independently of each other H, alkyl, alkenyl,alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl,polycarbocyclyl, heterocyclyl, aryl or heteroaryl, or R¹ and R² formtogether with the carbon atom they are bound to a carbocyclic orheterocyclic ring; X is OR or N(R)₂, where R is H, alkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl, Y is O or N substituted with anelectron-withdrawing group, and the nucleophilic catalyst is selectedfrom the group consisting of tertiary amines and tertiary phosphines;where the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl andheteroaryl groups R¹, R², R³ and R can carry one or more substituents.32. The method as claimed in claim 1, where the organic reaction is anucleophilic substitution reaction, where a compound R¹—X is reactedwith an alcohol R²—OH, a thiol R²—SH, a primary amine R³NH₂ or asecondary amine R³(R⁴)NH to a compound R¹—O—R², R¹—S—R², R¹—NH—R³ orR¹—N(R⁴)—R³, or a compound R¹(X)₂ is reacted with a primary amine R³NH₂to a cyclic compound; where R¹, R², R³ and R⁴, independently of eachother, are an alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl orheteroaryl group; and X is a halogenide or sulfonate group; where thealkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl orheteroaryl groups R¹, R², R³ and R⁴ can carry one or more substituents.33. The method as claimed in claim 1, where the organic reaction is anucleophilic aromatic substitution reaction, where a compound R¹—X isreacted with an alcohol R²—OH, a thiol R²—SH, a primary amine R³NH₂ or asecondary amine R³(R⁴)NH, where R¹ is a mono-, bi- or polycyclic aryl orheteroaryl group; X is a halide, and R², R³ and R⁴ are independently ofeach other an alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixedalkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixedcycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl orheteroaryl group, where the alkyl, alkenyl, alkapolyenyl, alkynyl,alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl,heterocyclyl, aryl, heteroaryl groups R¹, R², R³ and R⁴ can carry one ormore substituents.
 34. The method as claimed in claim 1, where theorganic reaction is the reduction of nitro compounds to thecorresponding amino compounds via reduction with a base metal,optionally in acidic solution; with a metal hydride, with a complexhydride, or with a borane; or via catalytic hydrogenation.
 35. Themethod as claimed in claim 34, where an aromatic or heteroaromatic nitrocompound R¹—NO₂, where R¹ is a mono-, bi- or polycyclic aryl orheteroaryl group, is reduced with Zn or Fe in acidic solution; or isreduced via catalytic hydrogenation in the presence of a hydrogenationcatalyst, where the hydrogenation catalyst comprises at least one metalof group VIII and/or VIIa selected from the group consisting ofruthenium, cobalt, rhodium, nickel, palladium, platinum and rhenium,where the hydrogenation catalyst is a heterogeneous hydrogenationcatalyst in which the metal is used in finely divided form, as a metalsponge or as a supported catalyst, or where the catalyst is ahomogeneous hydrogenation catalysts; where the aryl or heteroaryl groupR¹ can carry one or more substituents.
 36. The method as claimed inclaim 1, where the organic reaction is the reduction of C—C doublebonds.
 37. The method as claimed in claim 1, where the organic reactionis a reductive amination, where a primary or secondary amine is reactedwith an aldehyde or ketone in the presence of a reduction agent to anamino compound.
 38. The method as claimed in claim 1, which isadditionally carried out in the presence of a surfactant different fromthe cellulose derivative as defined in claim 1, where the surfactant isselected from the group consisting of anionic, cationic, nonionic andamphoteric surfactants, block polymers, polyelectrolytes, and mixturesthereof.
 39. The method as claimed in claim 38, where the surfactant isa polyoxyethanyl-α-tocopheryl succinate derivative.
 40. The method asclaimed in claim 1, where after completion of the organic reaction thecellulose derivative is precipitated by heating or by adding aninorganic salt, where the inorganic salt is selected from the groupconsisting of sodium sulfate, potassium sulfate, magnesium sulfate,ammonium sulfate, sodium phosphate, potassium phosphate, sodiumhydrogenphosphate, potassium hydrogenphosphate and sodium chloride;where precipitation of the cellulose derivative can be carried outbefore or after removing the reaction product and, if present, unreactedstarting compounds, and where the precipitated cellulose derivative,after a reactivation step, can be reused in the method as claimed inclaim 1.